除草剂阿特拉津对小鼠肝癌增殖转移能力影响的体内外研究
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摘要
研究背景：阿特拉津（ATR）是一种选择性内传导型的除草剂，适用于去除玉米、高梁、甘蔗、果园和茶园内的杂草，主要可防除一年生禾本科杂草以及阔叶杂草，同时对某些多年生杂草也具有一定的抑制作用。2005年，吉林省东辽河流域的旱田及非旱田水域中，ATR的平均值分别9.70μg/L和8.85μg/L。ATR难降解，可致畸变、突变和癌症，其进入土壤和河流后很难被微生物分解，因而在环境中不断蓄积，极大威胁人类健康和生态平衡。
ATR的特点是使用量大、残留期长、污染范围广。相关实验研究发现，ATR可使仓鼠染色体发生断裂，影响精子成熟过程，从而影响鼠的正常繁殖；以ATR处理小鼠，小鼠血液中白细胞减少，免疫系统发生异常，并发生肌肉痉挛；以ATR处理体外培养的人淋巴细胞，当ATR浓度为1×10-3μg/L时，可使核染色体发生轻微损坏，而ATR达到5×10-3μg/L时，染色体损伤显著。研究证实，ATR有致癌作用，长期暴露于ATR的实验动物可发生卵巢癌及乳腺癌。Su等的研究表明，ATR可作用于体内CYP19酶，改变其活性，继而干扰内分泌平衡，诱发癌症。关于ATR诱发肿瘤的机制，有报道称是由于ATR产生过氧化反应，导致正常细胞的氧化应激水平增加，由于细胞内氧自由基增加，导致线粒体和细胞核发生DNA损伤，继而正常细胞发生恶变，癌基因被激活。另外，ATR还具有其他生物学毒性，如生殖系统毒性、神经系统毒性、内分泌系统毒性和免疫系统毒性。
肝癌是一种恶性程度高、具有高转移性的肿瘤，原发性肝癌是全世界最常见恶性肿瘤之一，其死亡率在胃癌、食道癌之后，位居恶性肿瘤的第三位。我国是原发性肝细胞癌的高发区，每年死于肝癌的人数约占全世界肝癌死亡人数的50%。近20年来，虽然我国的肝癌治疗水平取得了长足进步，但肝癌的发病率和死亡率仍位于癌症的第二位。肝癌的发病原因较多，其中环境因素诱发的肝细胞恶变较为常见，主要是由于环境中的危险因子长期作用，刺激肿瘤的发生，如酒精和香烟等刺激可诱发肝炎，肝炎的长期作用易诱发肝癌。除草剂ATR作为肿瘤的危险分子，可能与肝癌的发生发展有关，其依据是：ATR难于降解并难于被土壤中的微生物所分解，因此导致农作物中的大量残留，未降解的ATR和作物中残留的ATR可被人体吸收并长期蓄积，造成肝脏负担加重，促进病变，继而可能导致肝细胞发生癌变。环境剂量的阿特拉津对肝癌细胞增殖、侵袭的影响尚未见报道。本研究主要探索ATR对肝癌细胞增殖及侵袭能力的影响，并探讨其机制，为农药ATR的正确使用及有效预防ATR的致瘤毒性提供实验基础，进而为ATR的环境预警与临床防治其生物毒性提供理论依据。
目的：通过体内外实验，观察除草剂阿特拉津对肝癌细胞H22增殖、侵袭和迁移能力的影响，并探讨其作用机制。
方法：选择鼠源性、恶性度高的肝腹水瘤H22细胞作为研究对象，构建小鼠肝原位移植瘤模型。将H22细胞或肝原位移植瘤模型小鼠分别暴露于不同浓度ATR，应用MTT法检测H22细胞的增殖能力，观察移植瘤的体积；应用免疫组化方法检测核增殖抗原PCNA的表达；应用流式细胞仪检测细胞周期，应用Real time PCR，Western blot方法检测周期相关基因P21、P53和Cyclin D1的转录和表达，分析ATR影响细胞周期的机制；应用Real time PCR， Western blot方法检测MMP9、MMP2及VEGF的表达，分析ATR影响细胞侵袭的机制；应用Western blot和Real time PCR检测STAT3信号通路及其下游基因C-myc的表达，分析ATR影响肿瘤细胞和原位移植瘤的信号通路。并利用免疫组化方法进一步验证上述基因和蛋白的表达及定位。
结果：0.01mmol/L、0.1mmol/L和1mmol/L的ATR作用H22细胞48h后，MTT结果显示ATR可促进肝癌细胞增殖，流式细胞仪检测结果显示ATR可促进细胞通过G0-G1期检查点，增加S期细胞的比率。成功构建肝脏原位移植瘤C57BL/6动物模型，给予20mg/kg和100mg/kg ATR灌胃处理小鼠后，小鼠肝脏原位移植瘤体积和重量增加，65%的肝脏原位移植瘤转移为腹水瘤，免疫组化结果显示细胞核中PCNA表达上调。体内外实验提示ATR可能通过下调肝癌细胞P53和P21基因的转录与表达，上调肝癌细胞Cyclin D1基因的转录和表达，促进细胞周期的进程。ATR作用后细胞的侵袭能力增强，肝脏原位移植瘤向腹水瘤转移的百分率增加，该作用可能是通过上调MMP2、MMP9和VEGF表达而实现的。而上述作用可能是通过ATR上调STAT3的表达，从而增加下游基因C-myc的表达。
结论：ATR可促进肝癌腹水瘤H22细胞的增殖、侵袭和迁移，并增加肝癌H22细胞存活率；促进原位移植瘤生长，增加原位肿瘤的重量，加速肝脏原位移植瘤向腹水瘤的转移。
ATR促进肝癌生长转移的作用机制可能是通过调节P21、 P53及Cyclin D1的表达，促进细胞周期进程，从而促进细胞的增殖；通过上调MMP2、MMP9和VEGF表达，促进H22细胞及其原位移植瘤的侵袭和转移，并促进新生血管形成。上述改变可能是通过激活STAT3信号通路及其下游基因C-myc而实现的。
Background: atrazine (ATR) is conducting the selective herbicide for corn,sugarcane, sorghum, tea plantations and orchards, etc. ATR can control annual grassesand broadleaf weeds, perennial certain miscellaneous grass also has a certain extent.2005statistics showed that the East Liaohe River in Jilin and non-upland uplandwaters, the annual average ATR were9.70μg/L and8.85μg/L. Atrazine is difficult todegrade, mutagenic, and carcinogenic distortion caused by chemical contaminants.ATR enters the soil and rivers difficult to balance the degradation and decomposed bymicroorganisms, resulting in their accumulation in the environment constantly, so agreat threat to human health and ecology. ATR is characterized by the use of a greatamount of residual period is very long, very wide range of pollution. Experimentalstudy found that in mice experiments, ATR hamster chromosome breakage can affectthe sperm maturation process, thus affecting the normal breeding rats. Another studyshowed ATR-treated mice, mouse blood leukopenia, abnormal immune and musclespasms, muscle contracture performance of acute poisoning, such as the nervoussystem. Furthermore, in vitro with human lymphocytes ATR using ATR concentration0.001μg/L, the resulting lymphocyte chromosome minor damage, the concentration0.005μg/L of chromosomal damage occurs significantly. Studies show that the foreignpart, ATR can make human carcinogen, long-term exposure can cause animals ATRovarian and breast cancer. Su et al found, ATR can affect the body CYP19enzymeactivity, thereby interfering with the endocrine balance, damages the body's endocrinesystem, causing a series of adverse symptoms, which will induce cancer, therefore,ATR has a priming effect of the tumor. ATR-induced mechanism of tumor has beenreported that due to the ATR produce peroxide, resulting in increased oxidative stressin normal cells, the cells due to the increase of oxygen free radicals, creating a viciouscycle, leading to mitochondrial and nuclear DNA damage in cells, normal cells turnmalignant oncogene is activated. In addition, other biological toxicity studies ATRalso includes nervous system toxicity, reproductive toxicity, endocrine system,immune system toxicity and toxicity. HCC is a highly malignant, with high metastatic tumors, and primary liver cancer is one of the most common malignancies worldwide,and its mortality rate, after qualifying in malignant gastric cancer, esophageal cancer,bit ranks third. Ours is a high incidence of hepatocellular carcinoma, China's annualdeaths from liver cancer, accounting for about50%of liver cancer deaths worldwide.The past20years, although the level of China's treatment of liver cancer has madeconsiderable progress, but liver cancer incidence and mortality of cancer is still insecond place. Its causes are many, including environmental factors induced malignanttransformation of liver cells, more common, mainly environmental risk factors in thelong-term effects, stimulate tumorigenesis, such as the liver, such as alcohol andcigarettes being stimulated after, it will induce the occurrence of hepatitis, andlong-term hepatitis will induce liver cancer. ATR herbicide molecules as dangerousdigestive tumors may be associated with the development of HCC. ATR is difficultdue to the degradation and decomposition by microorganisms in soil, in time to giveagricultural pesticide, resulting in residual ATR and other crops in a large number ofresidues, undegraded ATR and vegetables, will be absorbed by the body, the long-termaccumulation, causing liver burden, promote disease, which in turn is likely to makethe liver cells become cancerous. Environmental dose but whether ATR promotesproliferation and invasion of ovarian cancer cells has not been reported. In this study,to explore the effects of ATR on proliferation and invasion of ovarian cancer cells andto explore its mechanisms to provide a theoretical basis and experimental basis for theproper and effective use of preventive ATR ATR tumorigenic toxicity, and thus asatrazine and environmental warning prevention and treatment of its toxicity to providea scientific basis.
Objective: In vivo study outside herbicide atrazine on H22hepatoma cellproliferation, invasion and migration capabilities.
Methods: To study the effects of ATR on the body, we can choose to buildmurine orthotopic xenografts in mice, a higher degree of ascites tumor malignant cellline H22as the research object, which are used to build orthotopic liver tumor. TheH22cells were exposed to different concentrations of0.01mmol/L,0.1mmol/L, aftertreated by1mmol/L ATR for48h, detected by MTT proliferation of H22cells,immunohistochemical detection of cell proliferation antigen expression of PCNA;using flow H22detected the cell cycle, the application of real-time fluorescencequantitative-PCR, Western blotting was used to detect H22cells or liver orthotopic xenograft P21, P53, cyclin D1transcription and expression, and analysis of tumor cellcycle ATR mechanism; using real-time fluorescence quantitative expression-PCR,Western blotting detection MMP9, MMP2and VEGF, analysis ATR affect cellinvasion mechanisms and neovascularization capacity of marker genes and proteins;application of Western blotting and Real time PCR detection of STAT3signalingpathway and its downstream gene C-myc state analysis of the fundamentalmechanisms of tumor cells and in situ ATR xenografts. Similarly, the use ofimmunohistochemical methods in the cytoplasm and the nucleus is further validationof the expression of these genes and proteins.
Results: In vitro experiments, the concentration of0.01mmol/L,0.1mmol/L,ATR role1mmol/L of H22cells after48h, MTT showed that ATR can promote livercancer cell proliferation, flow cytometry showed that ATR can promote cell by G0-G1phase checkpoint, increasing the ratio of S phase cells; vitro experiments, orthotopicliver transplantation tumor was successfully constructed C57BL/6animal models,different concentrations20mg/kg and100mg/kg ATR orally treated mice, the resultsin mice orthotopic liver tumor volume and weight increase,65%of orthotopic livertumor metastasis into ascites tumor immunohistochemistry showed upregulation ofexpression of PCNA in the nucleus. ATR in vivo experiments confirmed bydown-regulating transcription and expression may P53and P21genes upregulatedCyclin D1gene and protein expression to promote cell cycle progression; ATR afterthe invasion ability of cells to enhance the role of liver ascites orthotopic xenografttumor metastasis to the percentage increase, which may be regulated by MMP2,MMP9and VEGF expression and realization. The above mechanism may be byupregulating the expression of STAT3, thereby increasing the expression ofdownstream genes C-myc-related genes and proteins.
Conclusion: In vitro experiments, the ATR doses did not cause apoptosis, and canpromote the proliferation of H22hepatoma ascites tumor cells, invasion and migration,and increase the survival rate of liver cancer H22cells. In vivo, ATR promoteorthotopic xenograft tumor growth, increase the weight of in situ tumors, acceleratedliver orthotopic xenograft tumor metastasis to ascites.Its mechanism of action is probably vitro and in vivo by regulating the expression ofP53, P21and Cyclin D1promotes cell cycle S increases, thereby contributing to theproliferation of H22cells and by promoting the expression of MMP2and VEGF promote H22cells and orthotopic transplantation tumor invasion and metastasis andpromote the formation of new blood vessels, regulates the expression of PCNA andpromote tumor cells in situ malignant proliferation. These changes may be through theactivation of STAT3signaling pathway and its downstream gene C-myc achieve.
ATR的特点是使用量大、残留期长、污染范围广。相关实验研究发现，ATR可使仓鼠染色体发生断裂，影响精子成熟过程，从而影响鼠的正常繁殖；以ATR处理小鼠，小鼠血液中白细胞减少，免疫系统发生异常，并发生肌肉痉挛；以ATR处理体外培养的人淋巴细胞，当ATR浓度为1×10-3μg/L时，可使核染色体发生轻微损坏，而ATR达到5×10-3μg/L时，染色体损伤显著。研究证实，ATR有致癌作用，长期暴露于ATR的实验动物可发生卵巢癌及乳腺癌。Su等的研究表明，ATR可作用于体内CYP19酶，改变其活性，继而干扰内分泌平衡，诱发癌症。关于ATR诱发肿瘤的机制，有报道称是由于ATR产生过氧化反应，导致正常细胞的氧化应激水平增加，由于细胞内氧自由基增加，导致线粒体和细胞核发生DNA损伤，继而正常细胞发生恶变，癌基因被激活。另外，ATR还具有其他生物学毒性，如生殖系统毒性、神经系统毒性、内分泌系统毒性和免疫系统毒性。
肝癌是一种恶性程度高、具有高转移性的肿瘤，原发性肝癌是全世界最常见恶性肿瘤之一，其死亡率在胃癌、食道癌之后，位居恶性肿瘤的第三位。我国是原发性肝细胞癌的高发区，每年死于肝癌的人数约占全世界肝癌死亡人数的50%。近20年来，虽然我国的肝癌治疗水平取得了长足进步，但肝癌的发病率和死亡率仍位于癌症的第二位。肝癌的发病原因较多，其中环境因素诱发的肝细胞恶变较为常见，主要是由于环境中的危险因子长期作用，刺激肿瘤的发生，如酒精和香烟等刺激可诱发肝炎，肝炎的长期作用易诱发肝癌。除草剂ATR作为肿瘤的危险分子，可能与肝癌的发生发展有关，其依据是：ATR难于降解并难于被土壤中的微生物所分解，因此导致农作物中的大量残留，未降解的ATR和作物中残留的ATR可被人体吸收并长期蓄积，造成肝脏负担加重，促进病变，继而可能导致肝细胞发生癌变。环境剂量的阿特拉津对肝癌细胞增殖、侵袭的影响尚未见报道。本研究主要探索ATR对肝癌细胞增殖及侵袭能力的影响，并探讨其机制，为农药ATR的正确使用及有效预防ATR的致瘤毒性提供实验基础，进而为ATR的环境预警与临床防治其生物毒性提供理论依据。
目的：通过体内外实验，观察除草剂阿特拉津对肝癌细胞H22增殖、侵袭和迁移能力的影响，并探讨其作用机制。
方法：选择鼠源性、恶性度高的肝腹水瘤H22细胞作为研究对象，构建小鼠肝原位移植瘤模型。将H22细胞或肝原位移植瘤模型小鼠分别暴露于不同浓度ATR，应用MTT法检测H22细胞的增殖能力，观察移植瘤的体积；应用免疫组化方法检测核增殖抗原PCNA的表达；应用流式细胞仪检测细胞周期，应用Real time PCR，Western blot方法检测周期相关基因P21、P53和Cyclin D1的转录和表达，分析ATR影响细胞周期的机制；应用Real time PCR， Western blot方法检测MMP9、MMP2及VEGF的表达，分析ATR影响细胞侵袭的机制；应用Western blot和Real time PCR检测STAT3信号通路及其下游基因C-myc的表达，分析ATR影响肿瘤细胞和原位移植瘤的信号通路。并利用免疫组化方法进一步验证上述基因和蛋白的表达及定位。
结果：0.01mmol/L、0.1mmol/L和1mmol/L的ATR作用H22细胞48h后，MTT结果显示ATR可促进肝癌细胞增殖，流式细胞仪检测结果显示ATR可促进细胞通过G0-G1期检查点，增加S期细胞的比率。成功构建肝脏原位移植瘤C57BL/6动物模型，给予20mg/kg和100mg/kg ATR灌胃处理小鼠后，小鼠肝脏原位移植瘤体积和重量增加，65%的肝脏原位移植瘤转移为腹水瘤，免疫组化结果显示细胞核中PCNA表达上调。体内外实验提示ATR可能通过下调肝癌细胞P53和P21基因的转录与表达，上调肝癌细胞Cyclin D1基因的转录和表达，促进细胞周期的进程。ATR作用后细胞的侵袭能力增强，肝脏原位移植瘤向腹水瘤转移的百分率增加，该作用可能是通过上调MMP2、MMP9和VEGF表达而实现的。而上述作用可能是通过ATR上调STAT3的表达，从而增加下游基因C-myc的表达。
结论：ATR可促进肝癌腹水瘤H22细胞的增殖、侵袭和迁移，并增加肝癌H22细胞存活率；促进原位移植瘤生长，增加原位肿瘤的重量，加速肝脏原位移植瘤向腹水瘤的转移。
ATR促进肝癌生长转移的作用机制可能是通过调节P21、 P53及Cyclin D1的表达，促进细胞周期进程，从而促进细胞的增殖；通过上调MMP2、MMP9和VEGF表达，促进H22细胞及其原位移植瘤的侵袭和转移，并促进新生血管形成。上述改变可能是通过激活STAT3信号通路及其下游基因C-myc而实现的。
Background: atrazine (ATR) is conducting the selective herbicide for corn,sugarcane, sorghum, tea plantations and orchards, etc. ATR can control annual grassesand broadleaf weeds, perennial certain miscellaneous grass also has a certain extent.2005statistics showed that the East Liaohe River in Jilin and non-upland uplandwaters, the annual average ATR were9.70μg/L and8.85μg/L. Atrazine is difficult todegrade, mutagenic, and carcinogenic distortion caused by chemical contaminants.ATR enters the soil and rivers difficult to balance the degradation and decomposed bymicroorganisms, resulting in their accumulation in the environment constantly, so agreat threat to human health and ecology. ATR is characterized by the use of a greatamount of residual period is very long, very wide range of pollution. Experimentalstudy found that in mice experiments, ATR hamster chromosome breakage can affectthe sperm maturation process, thus affecting the normal breeding rats. Another studyshowed ATR-treated mice, mouse blood leukopenia, abnormal immune and musclespasms, muscle contracture performance of acute poisoning, such as the nervoussystem. Furthermore, in vitro with human lymphocytes ATR using ATR concentration0.001μg/L, the resulting lymphocyte chromosome minor damage, the concentration0.005μg/L of chromosomal damage occurs significantly. Studies show that the foreignpart, ATR can make human carcinogen, long-term exposure can cause animals ATRovarian and breast cancer. Su et al found, ATR can affect the body CYP19enzymeactivity, thereby interfering with the endocrine balance, damages the body's endocrinesystem, causing a series of adverse symptoms, which will induce cancer, therefore,ATR has a priming effect of the tumor. ATR-induced mechanism of tumor has beenreported that due to the ATR produce peroxide, resulting in increased oxidative stressin normal cells, the cells due to the increase of oxygen free radicals, creating a viciouscycle, leading to mitochondrial and nuclear DNA damage in cells, normal cells turnmalignant oncogene is activated. In addition, other biological toxicity studies ATRalso includes nervous system toxicity, reproductive toxicity, endocrine system,immune system toxicity and toxicity. HCC is a highly malignant, with high metastatic tumors, and primary liver cancer is one of the most common malignancies worldwide,and its mortality rate, after qualifying in malignant gastric cancer, esophageal cancer,bit ranks third. Ours is a high incidence of hepatocellular carcinoma, China's annualdeaths from liver cancer, accounting for about50%of liver cancer deaths worldwide.The past20years, although the level of China's treatment of liver cancer has madeconsiderable progress, but liver cancer incidence and mortality of cancer is still insecond place. Its causes are many, including environmental factors induced malignanttransformation of liver cells, more common, mainly environmental risk factors in thelong-term effects, stimulate tumorigenesis, such as the liver, such as alcohol andcigarettes being stimulated after, it will induce the occurrence of hepatitis, andlong-term hepatitis will induce liver cancer. ATR herbicide molecules as dangerousdigestive tumors may be associated with the development of HCC. ATR is difficultdue to the degradation and decomposition by microorganisms in soil, in time to giveagricultural pesticide, resulting in residual ATR and other crops in a large number ofresidues, undegraded ATR and vegetables, will be absorbed by the body, the long-termaccumulation, causing liver burden, promote disease, which in turn is likely to makethe liver cells become cancerous. Environmental dose but whether ATR promotesproliferation and invasion of ovarian cancer cells has not been reported. In this study,to explore the effects of ATR on proliferation and invasion of ovarian cancer cells andto explore its mechanisms to provide a theoretical basis and experimental basis for theproper and effective use of preventive ATR ATR tumorigenic toxicity, and thus asatrazine and environmental warning prevention and treatment of its toxicity to providea scientific basis.
Objective: In vivo study outside herbicide atrazine on H22hepatoma cellproliferation, invasion and migration capabilities.
Methods: To study the effects of ATR on the body, we can choose to buildmurine orthotopic xenografts in mice, a higher degree of ascites tumor malignant cellline H22as the research object, which are used to build orthotopic liver tumor. TheH22cells were exposed to different concentrations of0.01mmol/L,0.1mmol/L, aftertreated by1mmol/L ATR for48h, detected by MTT proliferation of H22cells,immunohistochemical detection of cell proliferation antigen expression of PCNA;using flow H22detected the cell cycle, the application of real-time fluorescencequantitative-PCR, Western blotting was used to detect H22cells or liver orthotopic xenograft P21, P53, cyclin D1transcription and expression, and analysis of tumor cellcycle ATR mechanism; using real-time fluorescence quantitative expression-PCR,Western blotting detection MMP9, MMP2and VEGF, analysis ATR affect cellinvasion mechanisms and neovascularization capacity of marker genes and proteins;application of Western blotting and Real time PCR detection of STAT3signalingpathway and its downstream gene C-myc state analysis of the fundamentalmechanisms of tumor cells and in situ ATR xenografts. Similarly, the use ofimmunohistochemical methods in the cytoplasm and the nucleus is further validationof the expression of these genes and proteins.
Results: In vitro experiments, the concentration of0.01mmol/L,0.1mmol/L,ATR role1mmol/L of H22cells after48h, MTT showed that ATR can promote livercancer cell proliferation, flow cytometry showed that ATR can promote cell by G0-G1phase checkpoint, increasing the ratio of S phase cells; vitro experiments, orthotopicliver transplantation tumor was successfully constructed C57BL/6animal models,different concentrations20mg/kg and100mg/kg ATR orally treated mice, the resultsin mice orthotopic liver tumor volume and weight increase,65%of orthotopic livertumor metastasis into ascites tumor immunohistochemistry showed upregulation ofexpression of PCNA in the nucleus. ATR in vivo experiments confirmed bydown-regulating transcription and expression may P53and P21genes upregulatedCyclin D1gene and protein expression to promote cell cycle progression; ATR afterthe invasion ability of cells to enhance the role of liver ascites orthotopic xenografttumor metastasis to the percentage increase, which may be regulated by MMP2,MMP9and VEGF expression and realization. The above mechanism may be byupregulating the expression of STAT3, thereby increasing the expression ofdownstream genes C-myc-related genes and proteins.
Conclusion: In vitro experiments, the ATR doses did not cause apoptosis, and canpromote the proliferation of H22hepatoma ascites tumor cells, invasion and migration,and increase the survival rate of liver cancer H22cells. In vivo, ATR promoteorthotopic xenograft tumor growth, increase the weight of in situ tumors, acceleratedliver orthotopic xenograft tumor metastasis to ascites.Its mechanism of action is probably vitro and in vivo by regulating the expression ofP53, P21and Cyclin D1promotes cell cycle S increases, thereby contributing to theproliferation of H22cells and by promoting the expression of MMP2and VEGF promote H22cells and orthotopic transplantation tumor invasion and metastasis andpromote the formation of new blood vessels, regulates the expression of PCNA andpromote tumor cells in situ malignant proliferation. These changes may be through theactivation of STAT3signaling pathway and its downstream gene C-myc achieve.
引文
[1] Zhang Y, Wang M, Ren R, et al.[Effect of Atrazine on the content ofcalcium and expression of calmodulin in splenocytes of mice][J].Wei Sheng Yan Jiu.2008,37(5):584-586.
[2] Chen G, Lin W, Shen F, et al. Past HBV viral load as predictor ofmortality and morbidity from HCC and chronic liver disease in aprospective study[J]. Am J Gastroenterol.2006,101(8):1797-1803.
[3] Li P, Kim M M, Doshi J A. Comparison of the performance of theCMS Hierarchical Condition Category (CMS-HCC) risk adjusterwith the Charlson and Elixhauser comorbidity measures inpredicting mortality[J]. BMC Health Serv Res.2010,10:245.
[4] Jiang Y F, Yang Z H, Hu J Q. Recurrence or metastasis ofHCC:predictors, early detection and experimental antiangiogenictherapy[J]. World J Gastroenterol.2000,6(1):61-65.
[5] Turanli S. The value of resection of primary tumor in gastric cancerpatients with liver metastasis[J]. Indian J Surg.2010,72(3):200-205.
[6] Zhao Q, Wang Y, Cao Y, et al. Potential health risks of heavy metalsin cultivated topsoil and grain, including correlations with humanprimary liver, lung and gastric cancer, in Anhui province, EasternChina[J]. Sci Total Environ.2014,470-471:340-347.
[7] Kurihara N, Kubota T, Furukawa T, et al. Chemosensitivity testingof primary tumor cells from gastric cancer patients with livermetastasis can identify effective antitumor drugs[J]. AnticancerRes.1999,19(6B):5155-5158.
[8] Tada Y, Tabuchi Y, Saito Y.[Establishment of an experimentalmodel with a high frequency of liver metastasis and recurrencefrom gastric VX2cancer: histological analysis of thedevelopmental process of primary and metastatic cancer lesions][J].Nihon Geka Gakkai Zasshi.1992,93(8):818-826.
[9] Montomoli J, Erichsen R, Norgaard M, et al. Survival of patientswith primary liver cancer in central and northern Denmark,1998-2009[J]. Clin Epidemiol.2011,3Suppl1:3-10.
[10] Han X, Huang C X, Zhang H W, et al.[The occurrence and survivalcondition of primary liver cancer among residents in Yangpudistrict of Shanghai between year2002and2010][J]. Zhonghua YuFang Yi Xue Za Zhi.2012,46(2):119-124.
[11] Yang X B, Long S Q, Wu W Y, et al.[The distribution of Chinesemedicine syndrome types in primary liver cancer and theirdifferences of the survival time: a clinical study][J]. ZhongguoZhong Xi Yi Jie He Za Zhi.2013,33(7):911-914.
[12] Weinmann A, Koch S, Niederle I M, et al. Trends in Epidemiology,Treatment, and Survival of Hepatocellular Carcinoma PatientsBetween1998and2009: An Analysis of1066Cases of a GermanHCC Registry[J]. J Clin Gastroenterol.2014,48(3):279-289.
[13] Carr B I, Guerra V, Giannini E G, et al. Significance of platelet andAFP levels and liver function parameters for HCC size andsurvival[J]. Int J Biol Markers.2014:0.
[14] Akao M, Kuroda K, Gonoi T, et al. Isolation of a metastasizingcancer cell line from an aflatoxin B1-induced rat liver tumor[J].Chem Pharm Bull (Tokyo).1992,40(5):1299-1302.
[15] Lilleberg S L, Cabonce M A, Raju N R, et al. Alterations in the p53tumor suppressor gene in rat liver tumors induced by aflatoxinB1[J]. Prog Clin Biol Res.1992,376:203-222.
[16] Yokota T, Sizaret P, Martel N. Tumor-specific antigens on rat livercells transformed in vitro by chemical carcinogens[J]. J NatlCancer Inst.1978,60(1):125-129.
[17] Yokota T, Katahira S, Konno K, et al. Propionibacteriumacnes-mediated humoral immune responses to tumor-specificantigens on rat liver cells transformed in vitro by chemicalcarcinogens[J]. J Natl Cancer Inst.1978,61(6):1525-1529.
[18] Telang S, Tong C, Williams G M. Epigenetic membrane effects of apossible tumor promoting type on cultured liver cells by thenon-genotoxic organochlorine pesticides chlordane andheptachlor[J]. Carcinogenesis.1982,3(10):1175-1178.
[19] Lee K H, Liapi E, Ventura V P, et al. Evaluation of differentcalibrated spherical polyvinyl alcohol microspheres intranscatheter arterial chemoembolization: VX2tumor model inrabbit liver[J]. J Vasc Interv Radiol.2008,19(7):1065-1069.
[20] Fernandez-Checa J C, Colell A, Mari M, et al. Ceramide, tumornecrosis factor and alcohol-induced liver disease[J]. Alcohol ClinExp Res.2005,29(11Suppl):151S-157S.
[21] Nelson G M, Ahlborn G J, Allen J W, et al. Transcriptional changesassociated with reduced spontaneous liver tumor incidence in micechronically exposed to high dose arsenic[J]. Toxicology.2009,266(1-3):6-15.
[22] Moustafa M E, Carlson B A, Anver M R, et al. Selenium andselenoprotein deficiencies induce widespread pyogranulomaformation in mice, while high levels of dietary selenium decreaseliver tumor size driven by TGFalpha[J]. PLoS One.2013,8(2):e57389.
[23] Kim M S, Kim M S, Yoo N J, et al. Somatic mutation of SPOPtumor suppressor gene is rare in breast, lung, liver cancers, andacute leukemias[J]. APMIS.2014,122(2):164-166.
[24] Yamamoto H, Miyamoto Y, Nishihara Y, et al. Primarygastrointestinal stromal tumor of the liver with PDGFRA genemutation[J]. Hum Pathol.2010,41(4):605-609.
[25] Sarvary E, Nagy P, Benjamin A, et al. Mutation scanning of the p53tumor suppressor gene in renal and liver transplant patients inHungary[J]. Transplant Proc.2005,37(2):969-972.
[26] Liao C, Zhao M J, Zhao J, et al. Mutation analysis of novel humanliver-related putative tumor suppressor gene in hepatocellularcarcinoma[J]. World J Gastroenterol.2003,9(1):89-93.
[27] Cedrone A, Covino M, Caturelli E, et al. Utility ofalpha-fetoprotein (AFP) in the screening of patients withvirus-related chronic liver disease: does different viral etiologyinfluence AFP levels in HCC? A study in350western patients[J].Hepatogastroenterology.2000,47(36):1654-1658.
[28] Jackson L N, Evers B M. Regulation of proliferation, apoptosis andcell cycle in gastrointestinal disorders[J]. Curr Opin Pharmacol.2009,9(6):708-714.
[29] Benes F M. Regulation of cell cycle and DNA repair in post-mitoticGABA neurons in psychotic disorders[J]. Neuropharmacology.2011,60(7-8):1232-1242.
[30] Gunia S, Fritzsche F, May M, et al. Do different disorders in cellcycle regulation account for different biological behavior ofurothelial and sinonasal inverted papillomas?[J]. Pathobiology.2008,75(1):34-41.
[31] Ogawa R, Kodama T, Kurishima K, et al. Portal vein tumorthrombus of liver metastasis from lung cancer[J]. Acta Medica(Hradec Kralove).2009,52(4):163-166.
[32] Lee K F, Chu W, Lai P B. Portal vein tumor thrombus in colorectalliver metastasis[J]. Am J Surg.2005,190(3):364-365.
[33] Kyoda Y, Kobayashi K, Takahashi A, et al.[Liver metastasis withportal vein tumor thrombosis as a late recurrence of chromophoberenal cell carcinoma][J]. Hinyokika Kiyo.2009,55(1):23-25.
[34] Hatate K, Yamashita K, Hirai K, et al. Liver metastasis ofcolorectal cancer by protein-tyrosine phosphatase type4A,3(PRL-3) is mediated through lymph node metastasis and elevatedserum tumor markers such as CEA and CA19-9[J]. Oncol Rep.2008,20(4):737-743.
[35] Shindo Y, Hazama S, Maeda Y, et al.[A case of rectal carcinoidtumor with lymph node and liver metastasis5years after curativeresection][J]. Gan To Kagaku Ryoho.2013,40(12):2080-2082.
[36] Kinoshita H, Kinugasa S, Tsunemi K, et al.[A case of duodenalcarcinoid tumor accompanied by liver metastasis and lymph nodemetastases in a patient with von Recklinghausen disease][J]. NihonShokakibyo Gakkai Zasshi.2012,109(8):1379-1385.
[37] Pinheiro R S, Herman P, Lupinacci R M, et al. Tumor growthpattern as predictor of colorectal liver metastasis recurrence[J].Am J Surg.2013.
[38] Makino H, Kametaka H, Seike K, et al.[Resection of a synchronousliver metastasis from gastric cancer associated with portal veintumor thrombosis-a case report][J]. Gan To Kagaku Ryoho.2013,40(12):1843-1845.
[39] Murakami M, Ebisui C, Okada K, et al.[A case of liver and bonemetastasis from gastrointestinal stromal tumor treated usingimatinib][J]. Gan To Kagaku Ryoho.2014,41(1):99-101.
[40] Yamasaki K, Konno T, Ohtsuka N, et al.[A case of a solitarymetastasis on the surface of the liver by dissemination afterresection of an ovarian tumor][J]. Gan No Rinsho.1987,33(11):1374-1378.
[41] Moser G J, Meyer S A, Smart R C. The chlorinated pesticide mirexis a novel nonphorbol ester-type tumor promoter in mouse skin[J].Cancer Res.1992,52(3):631-636.
[42] Murali M E, Rajaran G M, Amirtha G D, et al. Elucidation oftumor-promoting potential of a combination pesticide byshort-term, in vivo bioassay[J]. J Environ Pathol Toxicol Oncol.2001,20(3):229-236.
[43] Ouyang Y H, Li S L, Song W, et al.[Effect of penehyclidinehydrochloride on tumor necrosis factor-alpha in liver and spleen inmice with acute organophosphorus pesticide poisoning][J].Zhongguo Wei Zhong Bing Ji Jiu Yi Xue.2010,22(4):238-239.
[44] Thakur C, Lu Y, Sun J, et al. Increased expression of mdig predictspoorer survival of the breast cancer patients[J]. Gene.2014,535(2):218-224.
[45] Sun J, Yu M, Lu Y, et al. Carcinogenic metalloid arsenic inducesexpression of mdig oncogene through JNK and STAT3activation[J].Cancer Lett.2014.
[46] Zhang Y, Lu Y, Yuan B Z, et al. The Human mineral dust-inducedgene, mdig, is a cell growth regulating gene associated with lungcancer[J]. Oncogene.2005,24(31):4873-4882.
[47] Chen B, Yu M, Chang Q, et al. Mdig de-represses H19largeintergenic non-coding RNA (lincRNA) by down-regulatingH3K9me3and heterochromatin[J]. Oncotarget.2013,4(9):1427-1437.
[48] Lu Y, Chang Q, Zhang Y, et al. Lung cancer-associated JmjCdomain protein mdig suppresses formation of tri-methyl lysine9ofhistone H3[J]. Cell Cycle.2009,8(13):2101-2109.
[49] Lasserre J P, Fack F, Revets D, et al. Effects of the endocrinedisruptors atrazine and PCB153on the protein expression ofMCF-7human cells[J]. J Proteome Res.2009,8(12):5485-5496.
[50] Yan D H, He Y, Wang H.[Environmental characteristics of theatrazine in the waters in East Liaohe River Basin][J]. Huan Jing KeXue.2005,26(3):203-208.
[51] Coban A, Filipov N M. Dopaminergic toxicity associated with oralexposure to the herbicide atrazine in juvenile male C57BL/6mice[J]. J Neurochem.2007,100(5):1177-1187.
[52] Chen J Y, Song Y, Zhang L S. Immunotoxicity of atrazine in Balb/cmice[J]. J Environ Sci Health B.2013,48(8):637-645.
[53] Li Y, Sun Y, Yang J, et al. The long-term effects of the herbicideatrazine on the dopaminergic system following exposure duringpubertal development[J]. Mutat Res.2014.
[54] Chromcova L, Blahova J, Plhalova L, et al. The effects of atrazineexposure on early life stages of common carp (Cyprinus carpio)[J].Neuro Endocrinol Lett.2013,34Suppl2:95-101.
[55] Sun Y, Li Y S, Yang J W, et al. Exposure to Atrazine duringGestation and Lactation Periods:Toxicity Effects on Dopamin-ergic Neurons in Offspring by Downregulation of Nurr1andVMAT2[J]. Int J Mol Sci.2014,15(2):2811-2825.
[56] Bardullas U, Giordano M, Rodriguez V M. Atrazine is primarilyresponsible for the toxicity of long-term exposure to a combinationof atrazine and inorganic arsenic in the nigrostriatal system of thealbino rat[J]. Neurotoxicol Teratol.2013,40:59-66.
[57] Zhao S, Liu J, Zhao F, et al. Sub-acute exposure to the herbicideatrazine suppresses cell immune functions in adolescent mice[J].Biosci Trends.2013,7(4):193-201.
[58] Lin Z, Dodd C A, Filipov N M. Short-term atrazine exposure causesbehavioral deficits and disrupts monoaminergic systems in maleC57BL/6mice[J]. Neurotoxicol Teratol.2013,39:26-35.
[59] Limousi F, Albouy-Llaty M, Carles C, et al. Does area deprivationmodify the association between exposure to a nitrate and low-doseatrazine metabolite mixture in drinking water and small forgestational age? A historic cohort study[J]. Environ Sci PollutRes Int.2013.
[60] Belloni V, Dessi-Fulgheri F, Zaccaroni M, et al. Early exposure tolow doses of atrazine affects behavior in juvenile and adult CD1mice[J]. Toxicology.2011,279(1-3):19-26.
[61] Coban A, Filipov N M. Dopaminergic toxicity associated with oralexposure to the herbicide atrazine in juvenile male C57BL/6mice[J]. J Neurochem.2007,100(5):1177-1187.
[62] Mitchkash M G, Mcpeek T, Boone M D. The effects of24-hexposure to carbaryl or atrazine on the locomotor performance andoverwinter growth and survival of juvenile spotted salamanders(Ambystoma maculatum)[J]. Environ Toxicol Chem.2014,33(3):548-552.
[63] Baxter L, Brain R, Prosser R, et al. Sensitivity of a green alga toatrazine is not enhanced by previous acute exposure[J]. EnvironPollut.2013,181:325-328.
[64] Nwani C D, Nagpure N S, Kumar R, et al. Induction of micronucleiand nuclear lesions in Channa punctatus following exposure tocarbosulfan, glyphosate and atrazine[J]. Drug Chem Toxicol.2013.
[65] Zhao S, Liu J, Zhao F, et al. Sub-acute exposure to the herbicideatrazine suppresses cell immune functions in adolescent mice[J].Biosci Trends.2013,7(4):193-201.
[66] Lin Z, Dodd C A, Filipov N M. Short-term atrazine exposure causesbehavioral deficits and disrupts monoaminergic systems in maleC57BL/6mice[J]. Neurotoxicol Teratol.2013,39:26-35.
[67] Jin Y, Wang L, Fu Z. Oral exposure to atrazine modulates hormonesynthesis and the transcription of steroidogenic genes in maleperipubertal mice[J]. Gen Comp Endocrinol.2013,184:120-127.
[68] Cimino-Reale G, Ferrario D, Casati B, et al. Combined in utero andjuvenile exposure of mice to arsenate and atrazine in drinkingwater modulates gene expression and clonogenicity of myeloidprogenitors[J]. Toxicol Lett.2008,180(1):59-66.
[69] Taets C, Aref S, Rayburn A L. The clastogenic potential of triazineherbicide combinations found in potable water supplies[J]. EnvironHealth Perspect.1998,106(4):197-201.
[70] Taets C, Rayburn A L. Coal fly ash exposure at agronomic levelsdoes not induce triploidy in maize[J]. Bull Environ Contam Toxicol.1996,56(5):690-695.
[71] Hayes T B, Anderson L L, Beasley V R, et al. Demasculinizationand feminization of male gonads by atrazine: consistent effectsacross vertebrate classes[J]. J Steroid Biochem Mol Biol.2011,127(1-2):64-73.
[72] Hayes T, Haston K, Tsui M, et al. Atrazine-inducedhermaphroditism at0.1ppb in American leopard frogs (Ranapipiens): laboratory and field evidence[J]. Environ Health Perspect.2003,111(4):568-575.
[73] Fan W, Yanase T, Morinaga H, et al. Atrazine-induced aromataseexpression is SF-1dependent: implications for endocrinedisruption in wildlife and reproductive cancers in humans[J].Environ Health Perspect.2007,115(5):720-727.
[74] Hayes T B, Khoury V, Narayan A, et al. Atrazine induces completefeminization and chemical castration in male African clawed frogs(Xenopus laevis)[J]. Proc Natl Acad Sci U S A.2010,107(10):4612-4617.
[75] Fan W, Yanase T, Morinaga H, et al. Herbicide atrazine activatesSF-1by direct affinity and concomitant co-activators recruitmentsto induce aromatase expression via promoter II[J]. BiochemBiophys Res Commun.2007,355(4):1012-1018.
[76] Fan W, Yanase T, Morinaga H, et al. Atrazine-induced aromataseexpression is SF-1dependent: implications for endocrinedisruption in wildlife and reproductive cancers in humans[J].Environ Health Perspect.2007,115(5):720-727.
[77] Van Meter R J, Swan C M. Road salts as environmental constraintsin urban pond food webs[J]. PLoS One.2014,9(2): e90168.
[78] Swan W I, Anchondo I M. Ethical selection of enteral and infantformula: demonstrating evidence-based practice and a responsiblevendor relationship[J]. J Acad Nutr Diet.2014,114(3):489-490.
[79] Lin N, Garry V F. In vitro studies of cellular and moleculardevelopmental toxicity of adjuvants, herbicides, and fungicidescommonly used in Red River Valley, Minnesota[J]. J ToxicolEnviron Health A.2000,60(6):423-439.
[80] Shi X, Richard J, Zirbes K M, et al. Cooperative interaction of Etv2and Gata2regulates the development of endothelial andhematopoietic lineages[J]. Dev Biol.2014.
[81] Mills C. One pill makes you smarter: an ethical appraisal of the riseof Ritalin[J]. Rep Inst Philos Public Policy.1998,18(4):13-17.
[82] Mills W J, Whaley R. Frostbite: experience with rapid rewarmingand ultrasonic therapy.1960-1[J]. Wilderness Environ Med.1998,9(4):226-247.
[83] Karrow N A, Guo T L, Delclos K B, et al. Nonylphenol alters theactivity of splenic NK cells and the numbers of leukocytesubpopulations in Sprague-Dawley rats: a two-generation feedingstudy[J]. Toxicology.2004,196(3):237-245.
[84] Munger B S, Whelan G P. Role of the American Board ofEmergency Medicine in the specialty of emergency medicine[J].Ann Emerg Med.1997,30(2):219-223.
[85] Wu T, Schwender H, Ruczinski I, et al. Evidence ofgene-environment interaction for two genes on chromosome4andenvironmental tobacco smoke in controlling the risk ofnonsyndromic cleft palate[J]. PLoS One.2014,9(2): e88088.
[86] Vermeeren A, Vuurman E F, Leufkens T R, et al. Residual Effectsof Low-Dose Sublingual Zolpidem on Highway DrivingPerformance the Morning after Middle-of-the-Night Use[J]. Sleep.2014,37(3):489-496.
[87] van Leeuwen J M.[Trends in research related to the health ofpigs][J]. Tijdschr Diergeneeskd.1988,113(21):1172-1180.
[88] van Leeuwen A F, Collewijn H, Erkelens C J. Dynamics ofhorizontal vergence movements: interaction with horizontal andvertical saccades and relation with monocular preferences[J].Vision Res.1998,38(24):3943-3954.
[89] Robutti F, Betta P G, Donna A, et al. A morphometrically-basedclassification rule for the diagnosis of primary mesotheliallesions[J]. J Pathol.1990,162(1):57-60.
[90] Snedeker J D, Kaplan S L, Dodge P R, et al. Subdural effusion andits relationship with neurologic sequelae of bacterial meningitis ininfancy: a prospective study[J]. Pediatrics.1990,86(2):163-170.
[91] Sathiakumar N, Delzell E, Morrisey M A, et al. Mortality followingbone metastasis and skeletal-related events among patients65years and above with lung cancer: A population-based analysis ofU.S. Medicare beneficiaries,1999-2006[J]. Lung India.2013,30(1):20-26.
[92] Meng W, Li X, Bai Z, et al. Silencing Alpha-Fetoprotein InhibitsVEGF and MMP-2/9Production in Human HepatocellularCarcinoma Cell[J]. PLoS One.2014,9(2): e90660.
[93] Ou Y R, Kang M, Zhou L.[Infection with L-form of Helicobacterpylori and expressions of MIF, MMP9and VEGF in gastriccarcinoma][J]. Nan Fang Yi Ke Da Xue Xue Bao.2014,34(2):180-187.
[94] Zhang Q W, Gan H Y, Cheng Z N, et al.[2-Deoxy-D-glucosecombined with Taxol inhibits VEGF expression and inducesapoptosis in orthotopically transplanted breast cancer in C3Hmice][J]. Nan Fang Yi Ke Da Xue Xue Bao.2014,34(2):193-196.
[95] Zhang Z L, Zhang J F, Yuan Y F, et al. Suppression of angiogenesisand tumor growth and using an anti-angiopoietin-2single-chainantibody[J]. Exp Ther Med.2014,7(3):543-552.
[96] Tuuminen R, Sahanne S, Loukovaara S. Low intravitrealangiopoietin-2and VEGF levels in vitrectomized diabetic patientswith simvastatin treatment[J]. Acta Ophthalmol.2014.
[97] Zhao Q, Caballero O L, Davis I D, et al. Tumor-specific isoformswitch of the fibroblast growth factor receptor2underlies themesenchymal and malignant phenotypes of clear cell renal cellcarcinomas[J]. Clin Cancer Res.2013,19(9):2460-2472.
[98] Li X, Wang Y, Zhao Y, et al. Immunotherapy of tumor with vaccinebased on basic fibroblast growth factor-activated fibroblasts[J]. JCancer Res Clin Oncol.2014,140(2):271-280.
[99] Salotti J, Dias M H, Koga M M, et al. Fibroblast growth factor2causes G2/M cell cycle arrest in ras-driven tumor cells through aSrc-dependent pathway[J]. PLoS One.2013,8(8): e72582.
[100] Kim J H, Frantz A M, Anderson K L, et al. Interleukin-8promotescanine hemangiosarcoma growth by regulating the tumormicroenvironment[J]. Exp Cell Res.2014.
[101] Nagaoka H, Iino Y, Takei H, et al. Platelet-derived endothelialcell growth factor/thymidine phosphorylase expression inmacrophages correlates with tumor angiogenesis and prognosis ininvasive breast cancer[J]. Int J Oncol.1998,13(3):449-454.
[102] Zhou J, Tang Z Y, Fan J, et al. Expression of platelet-derivedendothelial cell growth factor and vascular endothelial growthfactor in hepatocellular carcinoma and portal vein tumorthrombus[J]. J Cancer Res Clin Oncol.2000,126(1):57-61.
[103] Miszczak-Zaborska E, Smolarek M, Bartkowiak J.[Influence ofthe thymidine phosphorylase (platelet-derived endothelial cellgrowth factor) on tumor angiogenesis. Catalytic activity of enzymeinhibitors][J]. Postepy Biochem.2010,56(1):61-66.
[104] Martin M D, Matrisian L M. The other side of MMPs: protectiveroles in tumor progression[J]. Cancer Metastasis Rev.2007,26(3-4):717-724.
[105] Xiong T, Peng H, Chen G, et al. The expression and activity ofMMPs are increased in residual tumor tissues after the terminationof immunotherapy[J]. J Huazhong Univ Sci Technolog Med Sci.2008,28(4):375-378.
[106] Bourboulia D, Stetler-Stevenson W G. Matrix metalloproteinases(MMPs) and tissue inhibitors of metalloproteinases (TIMPs):Positive and negative regulators in tumor cell adhesion[J]. SeminCancer Biol.2010,20(3):161-168.
[107] Lukaszewicz-Zajac M, Mroczko B, Kornhuber J, et al. Matrixmetalloproteinases (MMPs) and their tissue inhibitors (TIMPs) inthe tumors of central nervous system (CNS)[J]. J Neural Transm.2013.
[108] Ribeiro B F, Iglesias D P, Nascimento G J, et al.Immunoexpression of MMPs-1,-2, and-9in ameloblastoma andodontogenic adenomatoid tumor[J]. Oral Dis.2009,15(7):472-477.
[109] Tian M, Wan Y, Tang J, et al. Depletion of tissue factorsuppresses hepatic metastasis and tumor growth in colorectalcancer via the downregulation of MMPs and the induction ofautophagy and apoptosis[J]. Cancer Biol Ther.2011,12(10):896-907.
[110] Nakamura T, Fukui M, Ebihara I, et al. Effects of low-protein dieton mRNA for ECM components, MMPs and TIMPs in glomeruli offocal glomerular sclerosis[J]. Contrib Nephrol.1994,107:146-155.
[111] Wang L, Xu Y X, Du XJ, et al. Dynamic expression profiles ofMMPs/TIMPs and collagen deposition in mechanically unloadedrat heart: implications for left ventricular assist devicesupport-induced cardiac alterations[J]. J Physiol Biochem.2013,69(3):477-485.
[112] Hassan Z K, Daghestani M H. Curcumin effect on MMPs andTIMPs genes in a breast cancer cell line[J]. Asian Pac J CancerPrev.2012,13(7):3259-3264.
[113] Meng W, Li X, Bai Z, et al. Silencing Alpha-Fetoprotein InhibitsVEGF and MMP-2/9Production in Human HepatocellularCarcinoma Cell[J]. PLoS One.2014,9(2): e90660.
[114] Fiorentini C, Bodei S, Bedussi F, et al. GPNMB/OA PROTEININCREASES THE INVASIVENESS OF HUMAN METASTATICPROSTATE CANCER CELL LINES DU145AND PC3THROUGHMMP-2AND MMP-9ACTIVITY[J]. Exp Cell Res.2014.
[115] Entschladen F, Zanker K S, Powe D G. Heterotrimeric G proteinsignaling in cancer cells with regard to metastasis formation[J].Cell Cycle.2011,10(7):1086-1091.
[116] Zhou Y, Guan X, Yu M, et al. Angiogenic/osteogenic response ofBMMSCs on bone-derived scaffold: Effect of hypoxia and role ofPI3K/Akt-mediated VEGF-VEGFR pathway[J]. Biotechnol J.2014.
[117] Mei J, Zhu X, Wang Z, et al. VEGFR, RET, and RAF/MEK/ERKPathway Take Part in the Inhibition of Osteosarcoma MG63Cellswith Sorafenib Treatment[J]. Cell Biochem Biophys.2013.
[118] Lin H C, Huang Y T, Yang Y Y, et al. Beneficial effects of dualVEGFR/FGFR inhibitor brivanib alaninate in cirrhotic portalhypertensive rats[J]. J Gastroenterol Hepatol.2013.
[119] Jin K, Li G, Cui B, et al. Assessment of a novel VEGF targetedagent using patient-derived tumor tissue xenograft models of coloncarcinoma with lymphatic and hepatic metastases[J]. PLoS One.2011,6(12): e28384.
[120] Moon J I, Kim J M, Jung G O, et al.[Expression of vascularendothelial growth factor (VEGF) family members and prognosisafter hepatic resection in HBV-related hepatocellularcarcinoma][J]. Korean J Hepatol.2008,14(2):185-196.
[121] Li H J, Wang J M, Tian Y T, et al.[Effect of matrine on Fas,VEGF, and activities of telomerase of MCF-7cells][J]. ZhongguoZhong Xi Yi Jie He Za Zhi.2013,33(9):1247-1251.
[122] Zhang Q W, Gan H Y, Cheng Z N, et al.[2-Deoxy-D-glucosecombined with Taxol inhibits VEGF expression and inducesapoptosis in orthotopically transplanted breast cancer in C3Hmice][J]. Nan Fang Yi Ke Da Xue Xue Bao.2014,34(2):193-196.
[123] Tseng P L, Tai M H, Huang C C, et al. Overexpression of VEGF isassociated with positive p53immunostaining in hepatocellularcarcinoma (HCC) and adverse outcome of HCC patients[J]. J SurgOncol.2008,98(5):349-357.
[124] Kim J H, Choi K Y, Lee D J, et al. Loss of Heterozygosities inFive Tumor Suppressor Genes (FHIT Gene, p16, pRb, E-Cadherinand p53) in Thyroid Tumors[J]. Clin Exp Otorhinolaryngol.2014,7(1):53-58.
[125] Feinmesser M, Halpern M, Fenig E, et al. Expression of theapoptosis-related oncogenes bcl-2, bax, and p53in Merkel cellcarcinoma: can they predict treatment response and clinicaloutcome?[J]. Hum Pathol.1999,30(11):1367-1372.
[126] Wang W, Johansson H, Bergholm U, et al. Apoptosis andExpression of the Proto-Oncogenes bcl-2and p53and theProliferation Factor Ki-67in Human Medullary ThyroidCarcinoma[J]. Endocr Pathol.1996,7(1):37-45.
[127] Sathornsumetee S, Desjardins A, Vredenburgh J J, et al. Phase IItrial of bevacizumab and erlotinib in patients with recurrentmalignant glioma[J]. Neuro Oncol.2010,12(12):1300-1310.
[128] Herbst R S, Johnson D H, Mininberg E, et al. Phase I/II trialevaluating the anti-vascular endothelial growth factor monoclonalantibody bevacizumab in combination with the HER-1/epidermalgrowth factor receptor tyrosine kinase inhibitor erlotinib forpatients with recurrent non-small-cell lung cancer[J]. J Clin Oncol.2005,23(11):2544-2555.
[129] Wen P Y, Chang S M, Lamborn K R, et al. Phase I/II study oferlotinib and temsirolimus for patients with recurrent malignantgliomas: North American Brain Tumor Consortium trial04-02[J].Neuro Oncol.2014.
[130] Fletcher S, Drewry J A, Shahani V M, et al. Molecular disruptionof oncogenic signal transducer and activator of transcription3(STAT3) protein[J]. Biochem Cell Biol.2009,87(6):825-833.
[131] Wheeler S E, Suzuki S, Thomas S M, et al. Epidermal growthfactor receptor variant III mediates head and neck cancer cellinvasion via STAT3activation[J]. Oncogene.2010,29(37):5135-5145.
[132] Huang C, Yang G, Jiang T, et al. Effects of IL-6and AG490onregulation of Stat3signaling pathway and invasion of humanpancreatic cancer cells in vitro[J]. J Exp Clin Cancer Res.2010,29:51.
[133] Ng D C, Lim C P, Lin B H, et al. SCG10-like protein (SCLIP) is aSTAT3-interacting protein involved in maintaining epithelialmorphology in MCF-7breast cancer cells[J]. Biochem J.2010,425(1):95-105.
[134] Rivat C, Rodrigues S, Bruyneel E, et al. Implication of STAT3signaling in human colonic cancer cells during intestinal trefoilfactor3(TFF3)--and vascular endothelial growth factor-mediatedcellular invasion and tumor growth[J]. Cancer Res.2005,65(1):195-202.
[135] Cascio S, D'Andrea A, Ferla R, et al. miR-20b modulates VEGFexpression by targeting HIF-1alpha and STAT3in MCF-7breastcancer cells[J]. J Cell Physiol.2010,224(1):242-249.
[136] Cheng G Z, Zhang W Z, Sun M, et al. Twist is transcriptionallyinduced by activation of STAT3and mediates STAT3oncogenicfunction[J]. J Biol Chem.2008,283(21):14665-14673.
[137] Bhardwaj A, Sethi G, Vadhan-Raj S, et al. Resveratrol inhibitsproliferation, induces apoptosis, and overcomes chemoresistancethrough down-regulation of STAT3and nuclearfactor-kappaB-regulated antiapoptotic and cell survival geneproducts in human multiple myeloma cells[J]. Blood.2007,109(6):2293-2302.
[138] Otero D C, Poli V, David M, et al. Cutting edge: inherent andacquired resistance to radiation-induced apoptosis in B cells: apivotal role for STAT3[J]. J Immunol.2006,177(10):6593-6597.
[139] Kim K W, Mutter R W, Cao C, et al. Inhibition of signaltransducer and activator of transcription3activity results indown-regulation of Survivin following irradiation[J]. Mol CancerTher.2006,5(11):2659-2665.
[140] Caldera V, Mellai M, Annovazzi L, et al. Stat3expression and itscorrelation with proliferation and apoptosis/autophagy ingliomas[J]. J Oncol.2008,2008:219241.
[141] Liu H J, Moroi Y, Masuda T, et al. Expression of phosphorylatedStat3, cyclin D1and Bcl-xL in extramammary Paget disease[J]. BrJ Dermatol.2006,154(5):926-932.
[142] Turkson J. STAT proteins as novel targets for cancer drugdiscovery[J]. Expert Opin Ther Targets.2004,8(5):409-422.
[143] Liang Q, Ma C, Zhao Y, et al. Inhibition of STAT3reducesastrocytoma cell invasion and constitutive activation of STAT3predicts poor prognosis in human astrocytoma[J]. PLoS One.2013,8(12): e84723.
[144] Xiong H, Du W, Wang J L, et al. Constitutive activation of STAT3is predictive of poor prognosis in human gastric cancer[J]. J MolMed (Berl).2012,90(9):1037-1046.
[145] Niu G, Bowman T, Huang M, et al. Roles of activated Src andStat3signaling in melanoma tumor cell growth[J]. Oncogene.2002,21(46):7001-7010.
[146] Baran-Marszak F, Boukhiar M, Harel S, et al. Constitutive andB-cell receptor-induced activation of STAT3are importantsignaling pathways targeted by bortezomib in leukemic mantle celllymphoma[J]. Haematologica.2010,95(11):1865-1872.
[147] Chung S S, Aroh C, Vadgama J V. Constitutive activation ofSTAT3signaling regulates hTERT and promotes stem cell-liketraits in human breast cancer cells[J]. PLoS One.2013,8(12):e83971.
[148] Grandis J R, Drenning S D, Zeng Q, et al. Constitutive activationof Stat3signaling abrogates apoptosis in squamous cellcarcinogenesis in vivo[J]. Proc Natl Acad Sci U S A.2000,97(8):4227-4232.
[149] Gao B, Shen X, Kunos G, et al. Constitutive activation ofJAK-STAT3signaling by BRCA1in human prostate cancercells[J]. FEBS Lett.2001,488(3):179-184.
[150] Wang Y, Ren X, Deng C, et al. Mechanism of the inhibition of theSTAT3signaling pathway by EGCG[J]. Oncol Rep.2013,30(6):2691-2696.
[151] Keasey M P, Kang S S, Lovins C, et al. Inhibition of a novelspecific neuroglial integrin signaling pathway increasesSTAT3-mediated CNTF expression[J]. Cell Commun Signal.2013,11(1):35.
[152] Seo C R, Yang D K, Song N J, et al. Cucurbitacin B andcucurbitacin I suppress adipocyte differentiation through inhibitionof STAT3signaling[J]. Food Chem Toxicol.2014,64:217-224.
[153] Kijima T, Niwa H, Steinman R A, et al. STAT3activationabrogates growth factor dependence and contributes to head andneck squamous cell carcinoma tumor growth in vivo[J]. CellGrowth Differ.2002,13(8):355-362.
[154] Fantin V R, Loboda A, Paweletz C P, et al. Constitutive activationof signal transducers and activators of transcription predictsvorinostat resistance in cutaneous T-cell lymphoma[J]. Cancer Res.2008,68(10):3785-3794.
[155] Woo S, Lee B L, Yoon J, et al. Constitutive activation of signaltransducers and activators of transcription3correlates with betterprognosis, cell proliferation and hypoxia-inducible factor-1alphain human gastric cancer[J]. Pathobiology.2011,78(6):295-301.
[156] Ishii H, Hulett M D, Li J M, et al. Yin Yang-1inhibits tumor cellgrowth and inhibits p21WAF1/Cip1complex formation with cdk4and cyclin D1[J]. Int J Oncol.2012,40(5):1575-1580.
[157] Lin D C, Shi Z Z, Xue L Y, et al.[Expression of cell cycle relatedproteins cyclin D1, p53and p21WAF1/Cip1in esophagealsquamous cell carcinoma][J]. Yi Chuan.2010,32(5):455-460.
[158] Dang C V. c-Myc target genes involved in cell growth, apoptosis,and metabolism[J]. Mol Cell Biol.1999,19(1):1-11.
[159] Prendergast G C. Mechanisms of apoptosis by c-Myc[J].Oncogene.1999,18(19):2967-2987.
[160] Sakamuro D, Eviner V, Elliott K J, et al. c-Myc induces apoptosisin epithelial cells by both p53-dependent and p53-independentmechanisms[J]. Oncogene.1995,11(11):2411-2418.
[161] Sellier H, Rebillard A, Guette C, et al. How should we defineSTAT3as an oncogene and as a potential target for therapy?[J].JAKSTAT.2013,2(3): e24716.
[162] Kijima T, Niwa H, Steinman R A, et al. STAT3activationabrogates growth factor dependence and contributes to head andneck squamous cell carcinoma tumor growth in vivo[J]. CellGrowth Differ.2002,13(8):355-362.
[163] Vogelstein B, Lane D, Levine A J. Surfing the p53network[J].Nature.2000,408(6810):307-310.
[164] Raman V, Martensen S A, Reisman D, et al. CompromisedHOXA5function can limit p53expression in human breasttumours[J]. Nature.2000,405(6789):974-978.
[165] Yu H, Jove R. The STATs of cancer--new molecular targets comeof age[J]. Nat Rev Cancer.2004,4(2):97-105.
[166] Folkman J. What is the evidence that tumors are angiogenesisdependent?[J]. J Natl Cancer Inst.1990,82(1):4-6.
[167] Hanahan D, Folkman J. Patterns and emerging mechanisms of theangiogenic switch during tumorigenesis[J]. Cell.1996,86(3):353-364.
[168] Rak J, Yu J L, Klement G, et al. Oncogenes and angiogenesis:signaling three-dimensional tumor growth[J]. J Investig DermatolSymp Proc.2000,5(1):24-33.
[169] Grunstein J, Roberts W G, Mathieu-Costello O, et al.Tumor-derived expression of vascular endothelial growth factor isa critical factor in tumor expansion and vascular function[J].Cancer Res.1999,59(7):1592-1598.
[170] Chakrabarti M, Banik N L, Ray S K. Photofrin basedphotodynamic therapy and miR-99a transfection inhibited FGFR3and PI3K/Akt signaling mechanisms to control growth of humanglioblastoma In vitro and in vivo[J]. PLoS One.2013,8(2):e55652.
[171] Millauer B, Shawver L K, Plate K H, et al. Glioblastoma growthinhibited in vivo by a dominant-negative Flk-1mutant[J]. Nature.1994,367(6463):576-579.
[172] Lohela M, Bry M, Tammela T, et al. VEGFs and receptorsinvolved in angiogenesis versus lymphangiogenesis[J]. Curr OpinCell Biol.2009,21(2):154-165.
[173] Wietecha M S, Dipietro L A. Therapeutic Approaches to theRegulation of Wound Angiogenesis[J]. Adv Wound Care (NewRochelle).2013,2(3):81-86.
[174] Zhou W, Wang G, Guo S. Regulation of angiogenesis via Notchsignaling in breast cancer and cancer stem cells[J]. BiochimBiophys Acta.2013,1836(2):304-320.
[175] Plein A, Fantin A, Ruhrberg C. Neuropilin regulation ofangiogenesis, arteriogenesis and vascular permeability[J].Microcirculation.2014.
[176] Jo D H, Kim J H, Kim K W, et al. Allosteric regulation ofpathologic angiogenesis: potential application forangiogenesis-related blindness[J]. Arch Pharm Res.2014,37(3):285-298.
[177] Niu G, Wright K L, Huang M, et al. Constitutive Stat3activityup-regulates VEGF expression and tumor angiogenesis[J].Oncogene.2002,21(13):2000-2008.
[178] Wei L H, Kuo M L, Chen C A, et al. Interleukin-6promotescervical tumor growth by VEGF-dependent angiogenesis via aSTAT3pathway[J]. Oncogene.2003,22(10):1517-1527.
[179] Bartoli M, Platt D, Lemtalsi T, et al. VEGF differentiallyactivates STAT3in microvascular endothelial cells[J]. FASEB J.2003,17(11):1562-1564.
[180] Ohotski J, Rosen H, Bittman R, et al. Sphingosine kinase2prevents the nuclear translocation of sphingosine1-phosphatereceptor-2and tyrosine416phosphorylated c-Src and increasesestrogen receptor negative MDA-MB-231breast cancer cell growth:The role of sphingosine1-phosphate receptor-4[J]. Cell Signal.2014,26(5):1040-1047.
[181] Yahata Y, Shirakata Y, Tokumaru S, et al. Nuclear translocationof phosphorylated STAT3is essential for vascular endothelialgrowth factor-induced human dermal microvascular endothelialcell migration and tube formation[J]. J Biol Chem.2003,278(41):40026-40031.
[182] Gong A, Zhang Z, Xiao D, et al. Localization of phosphorylatedTrkA in carrier vesicles involved in its nuclear translocation inU251cell line[J]. Sci China C Life Sci.2007,50(2):141-146.
[183] Deo D D, Axelrad T W, Robert E G, et al. Phosphorylation ofSTAT-3in response to basic fibroblast growth factor occursthrough a mechanism involving platelet-activating factor, JAK-2,and Src in human umbilical vein endothelial cells. Evidence for adual kinase mechanism[J]. J Biol Chem.2002,277(24):21237-21245.
[184] Holloway A C, Anger D A, Crankshaw D J, et al.Atrazine-induced changes in aromatase activity in estrogensensitive target tissues[J]. J Appl Toxicol.2008,28(3):260-270.
[185] Holloway A C, Anger D A, Crankshaw D J, et al.Atrazine-induced changes in aromatase activity in estrogensensitive target tissues[J]. J Appl Toxicol.2008,28(3):260-270.
[186] Grun F, Blumberg B. Perturbed nuclear receptor signaling byenvironmental obesogens as emerging factors in the obesitycrisis[J]. Rev Endocr Metab Disord.2007,8(2):161-171.
[187] Bays H, Blonde L, Rosenson R. Adiposopathy: how do diet,exercise and weight loss drug therapies improve metabolic diseasein overweight patients?[J]. Expert Rev Cardiovasc Ther.2006,4(6):871-895.
[188] Williams G. Aromatase up-regulation, insulin and raisedintracellular oestrogens in men, induce adiposity, metabolicsyndrome and prostate disease, via aberrant ER-alpha and GPERsignalling[J]. Mol Cell Endocrinol.2012,351(2):269-278.
[189] Mccauley L K, Tozum T F, Kozloff K M, et al. Transgenic modelsof metabolic bone disease: impact of estrogen receptor deficiencyon skeletal metabolism[J]. Connect Tissue Res.2003,44Suppl1:250-263.
[190] Hsia J, Bittner V, Tripputi M, et al. Metabolic syndrome andcoronary angiographic disease progression: the Women'sAngiographic Vitamin&Estrogen trial[J]. Am Heart J.2003,146(3):439-445.
[191] Lavranos G, Nikolaou A, Angelopoulou R. Octreotide inhibitsliver regeneration by suppressing regional estrogen receptor typea expression[J]. Hell J Nucl Med.2014,17Suppl1:56-61.
[192] de Vries H A, Ponds F A, Nieuwenhuijs V B, et al. Evidence thatestrogen receptors play a limited role in mediating enhancedrecovery of bile flow in female rats in the acute phase of liverischemia reperfusion injury[J]. Ann Hepatol.2013,12(1):130-137.
[193] Pedram A, Razandi M, O'Mahony F, et al. Estrogen reduces lipidcontent in the liver exclusively from membrane receptorsignaling[J]. Sci Signal.2013,6(276): a36.
[194] Zhang B, Wu Z Y. Estrogen derivatives: novel therapeutic agentsfor liver cirrhosis and portal hypertension[J]. Eur J GastroenterolHepatol.2013,25(3):263-270.
[195] Ahmed M A, Hassanein K M. Effects of estrogen onhyperglycemia and liver dysfunction in diabetic male rats[J]. Int JPhysiol Pathophysiol Pharmacol.2012,4(3):156-166.
[196] Humble J L, Saaristo M, Lindstrom K, et al. Effects of17alpha-ethinyl estradiol exposure on estrogen receptors alpha andbeta and vitellogenins A, B and C mRNA expression in the liver ofsand goby (Pomatoschistus minutus)[J]. Mar Environ Res.2014.
[197] Oberley T D, Oberley L W, Slattery A F, et al.Immunohistochemical localization of glutathione-S-transferase andglutathione peroxidase in adult Syrian hamster tissues and duringkidney development[J]. Am J Pathol.1991,139(2):355-369.
[198] Oberley T D, Slattery A F, Gonzalez A, et al. Comparativemorphologic and immunohistochemical studies of estrogen plusalpha-naphthoflavone-induced liver tumors in Syrian hamsters andrats[J]. Am J Pathol.1991,139(3):669-679.
[199] Ueda M, Imai T, Takizawa T, et al. Possible enhancing effects ofatrazine on growth of7,12-dimethylbenz(a) anthracene-inducedmammary tumors in ovariectomized Sprague-Dawley rats[J].Cancer Sci.2005,96(1):19-25.
[200] Albanito L, Lappano R, Madeo A, et al. Retraction:G-Protein-Coupled Receptor30and Estrogen Receptor-alpha AreInvolved in the Proliferative Effects Induced by Atrazine inOvarian Cancer Cells[J]. Environ Health Perspect.2014,122(2):A42.
[201] Albanito L, Lappano R, Madeo A, et al. G-protein-coupledreceptor30and estrogen receptor-alpha are involved in theproliferative effects induced by atrazine in ovarian cancer cells[J].Environ Health Perspect.2008,116(12):1648-1655.
[202] Adesiyan A C, Oyejola T O, Abarikwu S O, et al. Seleniumprovides protection to the liver but not the reproductive organs inan atrazine-model of experimental toxicity[J]. Exp Toxicol Pathol.2011,63(3):201-207.
[203] Kmetic I, Gaurina S V, Slivac I, et al. Atrazine exposuredecreases cell proliferation in Chinese Hamster Ovary (CHO-K1)cell line[J]. Bull Environ Contam Toxicol.2008,81(2):205-209.
[204] Velinov N, Poptodorov G, Gabrovski N, et al.[The role ofmatrixmetalloproteinases in the tumor growth and metastasis][J].Khirurgiia (Sofiia).2010(1):44-49.
[205] Albanito L, Lappano R, Madeo A, et al. Retraction:G-Protein-Coupled Receptor30and Estrogen Receptor-alpha AreInvolved in the Proliferative Effects Induced by Atrazine inOvarian Cancer Cells[J]. Environ Health Perspect.2014,122(2):A42.
[206] Albanito L, Lappano R, Madeo A, et al. G-protein-coupledreceptor30and estrogen receptor-alpha are involved in theproliferative effects induced by atrazine in ovarian cancer cells[J].Environ Health Perspect.2008,116(12):1648-1655.
[207] Sathiakumar N, Maclennan P A, Mandel J, et al. A review ofepidemiologic studies of triazine herbicides and cancer[J]. Crit RevToxicol.2011,41Suppl1:1-34.
[208] Sathiakumar N, Delzell E. A review of epidemiologic studies oftriazine herbicides and cancer[J]. Crit Rev Toxicol.1997,27(6):599-612.
[209] Inoue K, Torimura T, Nakamura T, et al. Vandetanib, an inhibitorof VEGF receptor-2and EGF receptor, suppresses tumordevelopment and improves prognosis of liver cancer in mice[J].Clin Cancer Res.2012,18(14):3924-3933.
[210] Bertin S, Mohsen-Kanson T, Baque P, et al. Tumormicroenvironment modifications induced by soluble VEGFreceptor expression in a rat liver metastasis model[J]. CancerLett.2010,298(2):264-272.
[211] Guo W J, Li J, Chen Z, et al. Transient increased expression ofVEGF and MMP-1in a rat liver tumor model after hepatic arterialocclusion[J]. Hepatogastroenterology.2004,51(56):381-386.
[212] Mukozu T, Nagai H, Matsui D, et al. Serum VEGF as a tumormarker in patients with HCV-related liver cirrhosis andhepatocellular carcinoma[J]. Anticancer Res.2013,33(3):1013-1021.
[213] Basappa, Ananda K C, Nanjunda S S, et al. Anti-tumor andanti-angiogenic activity of novel hydantoin derivatives: Inhibitionof VEGF secretion in liver metastatic osteosarcoma cells[J].Bioorg Med Chem.2009,17(14):4928-4934.
[214] Alavanja M C, Hoppin J A, Kamel F. Health effects of chronicpesticide exposure: cancer and neurotoxicity[J]. Annu Rev PublicHealth.2004,25:155-197.
[215] Jaga K, Dharmani C. The epidemiology of pesticide exposure andcancer: A review[J]. Rev Environ Health.2005,20(1):15-38.
[216] Wesseling C, Mcconnell R, Partanen T, et al. Agriculturalpesticide use in developing countries: health effects and researchneeds[J]. Int J Health Serv.1997,27(2):273-308.
[217] Moser G J, Meyer S A, Smart R C. The chlorinated pesticidemirex is a novel nonphorbol ester-type tumor promoter in mouseskin[J]. Cancer Res.1992,52(3):631-636.
[218] Murali M E, Rajaran G M, Amirtha G D, et al. Elucidation oftumor-promoting potential of a combination pesticide byshort-term, in vivo bioassay[J]. J Environ Pathol Toxicol Oncol.2001,20(3):229-236.
[219] Ouyang Y H, Li S L, Song W, et al.[Effect of penehyclidinehydrochloride on tumor necrosis factor-alpha in liver and spleen inmice with acute organophosphorus pesticide poisoning][J].Zhongguo Wei Zhong Bing Ji Jiu Yi Xue.2010,22(4):238-239.
[220] Pang L, Close M, Flintoft M. Degradation and sorption of atrazine,hexazinone and procymidone in coastal sand aquifer media[J].Pest Manag Sci.2005,61(2):133-143.
[221] Zeljezic D, Garaj-Vrhovac V. Genotoxicity evaluation ofpesticide formulations containing alachlor and atrazine in multiplemouse tissues (blood, kidney, liver, bone marrow, spleen) by cometassay[J]. Neoplasma.2004,51(3):198-203.
[222] Simpkins J W, Swenberg J A, Weiss N, et al. Atrazine and breastcancer: a framework assessment of the toxicological andepidemiological evidence[J]. Toxicol Sci.2011,123(2):441-459.
[223] Rajkovic V, Kovac R, Koledin I, et al. Atrazine-induced changesin the myocardial structure of peripubertal rats[J]. Toxicol IndHealth.2012.
[224] Holloway A C, Anger D A, Crankshaw D J, et al.Atrazine-induced changes in aromatase activity in estrogensensitive target tissues[J]. J Appl Toxicol.2008,28(3):260-270.
[225] Wincewicz A, Baltaziak M, Kanczuga-Koda L, et al. STAT3andapoptosis regulators: Bak and Bcl-xL in endometrioidadenocarcinomas of different estrogen receptor-alphaimmunoprofile[J]. Gynecol Endocrinol.2011,27(8):536-540.
[226] Mitra R, Guo Z, Milani M, et al. CYP3A4mediates growth ofestrogen receptor-positive breast cancer cells in part by inducingnuclear translocation of phospho-Stat3through biosynthesis of(+/-)-14,15-epoxyeicosatrienoic acid (EET)[J]. J Biol Chem.2011,286(20):17543-17559.
[227] Gao Q, Mezei G, Nie Y, et al. Anorectic estrogen mimics leptin'seffect on the rewiring of melanocortin cells and Stat3signaling inobese animals[J]. Nat Med.2007,13(1):89-94.
[228] Wang L H, Yang X Y, Mihalic K, et al. Activation of estrogenreceptor blocks interleukin-6-inducible cell growth of humanmultiple myeloma involving molecular cross-talk between estrogenreceptor and STAT3mediated by co-regulator PIAS3[J]. J BiolChem.2001,276(34):31839-31844.
[229] Zahid M, Beseler C L, Hall J B, et al. Unbalanced estrogenmetabolism in ovarian cancer[J]. Int J Cancer.2013.
[230] Fuente-Martin E, Garcia-Caceres C, Morselli E, et al. Estrogen,astrocytes and the neuroendocrine control of metabolism[J]. RevEndocr Metab Disord.2013,14(4):331-338.
[231] Sharma K L, Agarwal A, Misra S, et al. Association of geneticvariants of xenobiotic and estrogen metabolism pathway (CYP1A1and CYP1B1) with gallbladder cancer susceptibility[J]. TumourBiol.2014.
[232] Fortner R T, Oh H, Daugherty S E, et al. Analgesic Use andPatterns of Estrogen Metabolism in Premenopausal Women[J].Horm Cancer.2014.
[233] Demaria M, Camporeale A, Poli V. STAT3and metabolism: Howmany ways to use a single molecule?[J]. Int J Cancer.2014.
[234] Kinoshita S, Ogawa W, Okamoto Y, et al. Role of hepatic STAT3in the regulation of lipid metabolism[J]. Kobe J Med Sci.2008,54(4): E200-E208.
[235] Liu J, Jing X, Gan L, et al. The JAK2/STAT3signal pathwayregulates the expression of genes related to skeletal muscledevelopment and energy metabolism in mice and mouse skeletalmuscle cells[J]. Biosci Biotechnol Biochem.2012,76(10):1866-1870.
[236] Bravard A, Vial G, Chauvin M A, et al. FTO contributes to hepaticmetabolism regulation through regulation of leptin action andSTAT3signalling in liver[J]. Cell Commun Signal.2014,12:4.
[237] Jowa L, Howd R. Should atrazine and related chlorotriazines beconsidered carcinogenic for human health risk assessment?[J]. JEnviron Sci Health C Environ Carcinog Ecotoxicol Rev.2011,29(2):91-144.
[2] Chen G, Lin W, Shen F, et al. Past HBV viral load as predictor ofmortality and morbidity from HCC and chronic liver disease in aprospective study[J]. Am J Gastroenterol.2006,101(8):1797-1803.
[3] Li P, Kim M M, Doshi J A. Comparison of the performance of theCMS Hierarchical Condition Category (CMS-HCC) risk adjusterwith the Charlson and Elixhauser comorbidity measures inpredicting mortality[J]. BMC Health Serv Res.2010,10:245.
[4] Jiang Y F, Yang Z H, Hu J Q. Recurrence or metastasis ofHCC:predictors, early detection and experimental antiangiogenictherapy[J]. World J Gastroenterol.2000,6(1):61-65.
[5] Turanli S. The value of resection of primary tumor in gastric cancerpatients with liver metastasis[J]. Indian J Surg.2010,72(3):200-205.
[6] Zhao Q, Wang Y, Cao Y, et al. Potential health risks of heavy metalsin cultivated topsoil and grain, including correlations with humanprimary liver, lung and gastric cancer, in Anhui province, EasternChina[J]. Sci Total Environ.2014,470-471:340-347.
[7] Kurihara N, Kubota T, Furukawa T, et al. Chemosensitivity testingof primary tumor cells from gastric cancer patients with livermetastasis can identify effective antitumor drugs[J]. AnticancerRes.1999,19(6B):5155-5158.
[8] Tada Y, Tabuchi Y, Saito Y.[Establishment of an experimentalmodel with a high frequency of liver metastasis and recurrencefrom gastric VX2cancer: histological analysis of thedevelopmental process of primary and metastatic cancer lesions][J].Nihon Geka Gakkai Zasshi.1992,93(8):818-826.
[9] Montomoli J, Erichsen R, Norgaard M, et al. Survival of patientswith primary liver cancer in central and northern Denmark,1998-2009[J]. Clin Epidemiol.2011,3Suppl1:3-10.
[10] Han X, Huang C X, Zhang H W, et al.[The occurrence and survivalcondition of primary liver cancer among residents in Yangpudistrict of Shanghai between year2002and2010][J]. Zhonghua YuFang Yi Xue Za Zhi.2012,46(2):119-124.
[11] Yang X B, Long S Q, Wu W Y, et al.[The distribution of Chinesemedicine syndrome types in primary liver cancer and theirdifferences of the survival time: a clinical study][J]. ZhongguoZhong Xi Yi Jie He Za Zhi.2013,33(7):911-914.
[12] Weinmann A, Koch S, Niederle I M, et al. Trends in Epidemiology,Treatment, and Survival of Hepatocellular Carcinoma PatientsBetween1998and2009: An Analysis of1066Cases of a GermanHCC Registry[J]. J Clin Gastroenterol.2014,48(3):279-289.
[13] Carr B I, Guerra V, Giannini E G, et al. Significance of platelet andAFP levels and liver function parameters for HCC size andsurvival[J]. Int J Biol Markers.2014:0.
[14] Akao M, Kuroda K, Gonoi T, et al. Isolation of a metastasizingcancer cell line from an aflatoxin B1-induced rat liver tumor[J].Chem Pharm Bull (Tokyo).1992,40(5):1299-1302.
[15] Lilleberg S L, Cabonce M A, Raju N R, et al. Alterations in the p53tumor suppressor gene in rat liver tumors induced by aflatoxinB1[J]. Prog Clin Biol Res.1992,376:203-222.
[16] Yokota T, Sizaret P, Martel N. Tumor-specific antigens on rat livercells transformed in vitro by chemical carcinogens[J]. J NatlCancer Inst.1978,60(1):125-129.
[17] Yokota T, Katahira S, Konno K, et al. Propionibacteriumacnes-mediated humoral immune responses to tumor-specificantigens on rat liver cells transformed in vitro by chemicalcarcinogens[J]. J Natl Cancer Inst.1978,61(6):1525-1529.
[18] Telang S, Tong C, Williams G M. Epigenetic membrane effects of apossible tumor promoting type on cultured liver cells by thenon-genotoxic organochlorine pesticides chlordane andheptachlor[J]. Carcinogenesis.1982,3(10):1175-1178.
[19] Lee K H, Liapi E, Ventura V P, et al. Evaluation of differentcalibrated spherical polyvinyl alcohol microspheres intranscatheter arterial chemoembolization: VX2tumor model inrabbit liver[J]. J Vasc Interv Radiol.2008,19(7):1065-1069.
[20] Fernandez-Checa J C, Colell A, Mari M, et al. Ceramide, tumornecrosis factor and alcohol-induced liver disease[J]. Alcohol ClinExp Res.2005,29(11Suppl):151S-157S.
[21] Nelson G M, Ahlborn G J, Allen J W, et al. Transcriptional changesassociated with reduced spontaneous liver tumor incidence in micechronically exposed to high dose arsenic[J]. Toxicology.2009,266(1-3):6-15.
[22] Moustafa M E, Carlson B A, Anver M R, et al. Selenium andselenoprotein deficiencies induce widespread pyogranulomaformation in mice, while high levels of dietary selenium decreaseliver tumor size driven by TGFalpha[J]. PLoS One.2013,8(2):e57389.
[23] Kim M S, Kim M S, Yoo N J, et al. Somatic mutation of SPOPtumor suppressor gene is rare in breast, lung, liver cancers, andacute leukemias[J]. APMIS.2014,122(2):164-166.
[24] Yamamoto H, Miyamoto Y, Nishihara Y, et al. Primarygastrointestinal stromal tumor of the liver with PDGFRA genemutation[J]. Hum Pathol.2010,41(4):605-609.
[25] Sarvary E, Nagy P, Benjamin A, et al. Mutation scanning of the p53tumor suppressor gene in renal and liver transplant patients inHungary[J]. Transplant Proc.2005,37(2):969-972.
[26] Liao C, Zhao M J, Zhao J, et al. Mutation analysis of novel humanliver-related putative tumor suppressor gene in hepatocellularcarcinoma[J]. World J Gastroenterol.2003,9(1):89-93.
[27] Cedrone A, Covino M, Caturelli E, et al. Utility ofalpha-fetoprotein (AFP) in the screening of patients withvirus-related chronic liver disease: does different viral etiologyinfluence AFP levels in HCC? A study in350western patients[J].Hepatogastroenterology.2000,47(36):1654-1658.
[28] Jackson L N, Evers B M. Regulation of proliferation, apoptosis andcell cycle in gastrointestinal disorders[J]. Curr Opin Pharmacol.2009,9(6):708-714.
[29] Benes F M. Regulation of cell cycle and DNA repair in post-mitoticGABA neurons in psychotic disorders[J]. Neuropharmacology.2011,60(7-8):1232-1242.
[30] Gunia S, Fritzsche F, May M, et al. Do different disorders in cellcycle regulation account for different biological behavior ofurothelial and sinonasal inverted papillomas?[J]. Pathobiology.2008,75(1):34-41.
[31] Ogawa R, Kodama T, Kurishima K, et al. Portal vein tumorthrombus of liver metastasis from lung cancer[J]. Acta Medica(Hradec Kralove).2009,52(4):163-166.
[32] Lee K F, Chu W, Lai P B. Portal vein tumor thrombus in colorectalliver metastasis[J]. Am J Surg.2005,190(3):364-365.
[33] Kyoda Y, Kobayashi K, Takahashi A, et al.[Liver metastasis withportal vein tumor thrombosis as a late recurrence of chromophoberenal cell carcinoma][J]. Hinyokika Kiyo.2009,55(1):23-25.
[34] Hatate K, Yamashita K, Hirai K, et al. Liver metastasis ofcolorectal cancer by protein-tyrosine phosphatase type4A,3(PRL-3) is mediated through lymph node metastasis and elevatedserum tumor markers such as CEA and CA19-9[J]. Oncol Rep.2008,20(4):737-743.
[35] Shindo Y, Hazama S, Maeda Y, et al.[A case of rectal carcinoidtumor with lymph node and liver metastasis5years after curativeresection][J]. Gan To Kagaku Ryoho.2013,40(12):2080-2082.
[36] Kinoshita H, Kinugasa S, Tsunemi K, et al.[A case of duodenalcarcinoid tumor accompanied by liver metastasis and lymph nodemetastases in a patient with von Recklinghausen disease][J]. NihonShokakibyo Gakkai Zasshi.2012,109(8):1379-1385.
[37] Pinheiro R S, Herman P, Lupinacci R M, et al. Tumor growthpattern as predictor of colorectal liver metastasis recurrence[J].Am J Surg.2013.
[38] Makino H, Kametaka H, Seike K, et al.[Resection of a synchronousliver metastasis from gastric cancer associated with portal veintumor thrombosis-a case report][J]. Gan To Kagaku Ryoho.2013,40(12):1843-1845.
[39] Murakami M, Ebisui C, Okada K, et al.[A case of liver and bonemetastasis from gastrointestinal stromal tumor treated usingimatinib][J]. Gan To Kagaku Ryoho.2014,41(1):99-101.
[40] Yamasaki K, Konno T, Ohtsuka N, et al.[A case of a solitarymetastasis on the surface of the liver by dissemination afterresection of an ovarian tumor][J]. Gan No Rinsho.1987,33(11):1374-1378.
[41] Moser G J, Meyer S A, Smart R C. The chlorinated pesticide mirexis a novel nonphorbol ester-type tumor promoter in mouse skin[J].Cancer Res.1992,52(3):631-636.
[42] Murali M E, Rajaran G M, Amirtha G D, et al. Elucidation oftumor-promoting potential of a combination pesticide byshort-term, in vivo bioassay[J]. J Environ Pathol Toxicol Oncol.2001,20(3):229-236.
[43] Ouyang Y H, Li S L, Song W, et al.[Effect of penehyclidinehydrochloride on tumor necrosis factor-alpha in liver and spleen inmice with acute organophosphorus pesticide poisoning][J].Zhongguo Wei Zhong Bing Ji Jiu Yi Xue.2010,22(4):238-239.
[44] Thakur C, Lu Y, Sun J, et al. Increased expression of mdig predictspoorer survival of the breast cancer patients[J]. Gene.2014,535(2):218-224.
[45] Sun J, Yu M, Lu Y, et al. Carcinogenic metalloid arsenic inducesexpression of mdig oncogene through JNK and STAT3activation[J].Cancer Lett.2014.
[46] Zhang Y, Lu Y, Yuan B Z, et al. The Human mineral dust-inducedgene, mdig, is a cell growth regulating gene associated with lungcancer[J]. Oncogene.2005,24(31):4873-4882.
[47] Chen B, Yu M, Chang Q, et al. Mdig de-represses H19largeintergenic non-coding RNA (lincRNA) by down-regulatingH3K9me3and heterochromatin[J]. Oncotarget.2013,4(9):1427-1437.
[48] Lu Y, Chang Q, Zhang Y, et al. Lung cancer-associated JmjCdomain protein mdig suppresses formation of tri-methyl lysine9ofhistone H3[J]. Cell Cycle.2009,8(13):2101-2109.
[49] Lasserre J P, Fack F, Revets D, et al. Effects of the endocrinedisruptors atrazine and PCB153on the protein expression ofMCF-7human cells[J]. J Proteome Res.2009,8(12):5485-5496.
[50] Yan D H, He Y, Wang H.[Environmental characteristics of theatrazine in the waters in East Liaohe River Basin][J]. Huan Jing KeXue.2005,26(3):203-208.
[51] Coban A, Filipov N M. Dopaminergic toxicity associated with oralexposure to the herbicide atrazine in juvenile male C57BL/6mice[J]. J Neurochem.2007,100(5):1177-1187.
[52] Chen J Y, Song Y, Zhang L S. Immunotoxicity of atrazine in Balb/cmice[J]. J Environ Sci Health B.2013,48(8):637-645.
[53] Li Y, Sun Y, Yang J, et al. The long-term effects of the herbicideatrazine on the dopaminergic system following exposure duringpubertal development[J]. Mutat Res.2014.
[54] Chromcova L, Blahova J, Plhalova L, et al. The effects of atrazineexposure on early life stages of common carp (Cyprinus carpio)[J].Neuro Endocrinol Lett.2013,34Suppl2:95-101.
[55] Sun Y, Li Y S, Yang J W, et al. Exposure to Atrazine duringGestation and Lactation Periods:Toxicity Effects on Dopamin-ergic Neurons in Offspring by Downregulation of Nurr1andVMAT2[J]. Int J Mol Sci.2014,15(2):2811-2825.
[56] Bardullas U, Giordano M, Rodriguez V M. Atrazine is primarilyresponsible for the toxicity of long-term exposure to a combinationof atrazine and inorganic arsenic in the nigrostriatal system of thealbino rat[J]. Neurotoxicol Teratol.2013,40:59-66.
[57] Zhao S, Liu J, Zhao F, et al. Sub-acute exposure to the herbicideatrazine suppresses cell immune functions in adolescent mice[J].Biosci Trends.2013,7(4):193-201.
[58] Lin Z, Dodd C A, Filipov N M. Short-term atrazine exposure causesbehavioral deficits and disrupts monoaminergic systems in maleC57BL/6mice[J]. Neurotoxicol Teratol.2013,39:26-35.
[59] Limousi F, Albouy-Llaty M, Carles C, et al. Does area deprivationmodify the association between exposure to a nitrate and low-doseatrazine metabolite mixture in drinking water and small forgestational age? A historic cohort study[J]. Environ Sci PollutRes Int.2013.
[60] Belloni V, Dessi-Fulgheri F, Zaccaroni M, et al. Early exposure tolow doses of atrazine affects behavior in juvenile and adult CD1mice[J]. Toxicology.2011,279(1-3):19-26.
[61] Coban A, Filipov N M. Dopaminergic toxicity associated with oralexposure to the herbicide atrazine in juvenile male C57BL/6mice[J]. J Neurochem.2007,100(5):1177-1187.
[62] Mitchkash M G, Mcpeek T, Boone M D. The effects of24-hexposure to carbaryl or atrazine on the locomotor performance andoverwinter growth and survival of juvenile spotted salamanders(Ambystoma maculatum)[J]. Environ Toxicol Chem.2014,33(3):548-552.
[63] Baxter L, Brain R, Prosser R, et al. Sensitivity of a green alga toatrazine is not enhanced by previous acute exposure[J]. EnvironPollut.2013,181:325-328.
[64] Nwani C D, Nagpure N S, Kumar R, et al. Induction of micronucleiand nuclear lesions in Channa punctatus following exposure tocarbosulfan, glyphosate and atrazine[J]. Drug Chem Toxicol.2013.
[65] Zhao S, Liu J, Zhao F, et al. Sub-acute exposure to the herbicideatrazine suppresses cell immune functions in adolescent mice[J].Biosci Trends.2013,7(4):193-201.
[66] Lin Z, Dodd C A, Filipov N M. Short-term atrazine exposure causesbehavioral deficits and disrupts monoaminergic systems in maleC57BL/6mice[J]. Neurotoxicol Teratol.2013,39:26-35.
[67] Jin Y, Wang L, Fu Z. Oral exposure to atrazine modulates hormonesynthesis and the transcription of steroidogenic genes in maleperipubertal mice[J]. Gen Comp Endocrinol.2013,184:120-127.
[68] Cimino-Reale G, Ferrario D, Casati B, et al. Combined in utero andjuvenile exposure of mice to arsenate and atrazine in drinkingwater modulates gene expression and clonogenicity of myeloidprogenitors[J]. Toxicol Lett.2008,180(1):59-66.
[69] Taets C, Aref S, Rayburn A L. The clastogenic potential of triazineherbicide combinations found in potable water supplies[J]. EnvironHealth Perspect.1998,106(4):197-201.
[70] Taets C, Rayburn A L. Coal fly ash exposure at agronomic levelsdoes not induce triploidy in maize[J]. Bull Environ Contam Toxicol.1996,56(5):690-695.
[71] Hayes T B, Anderson L L, Beasley V R, et al. Demasculinizationand feminization of male gonads by atrazine: consistent effectsacross vertebrate classes[J]. J Steroid Biochem Mol Biol.2011,127(1-2):64-73.
[72] Hayes T, Haston K, Tsui M, et al. Atrazine-inducedhermaphroditism at0.1ppb in American leopard frogs (Ranapipiens): laboratory and field evidence[J]. Environ Health Perspect.2003,111(4):568-575.
[73] Fan W, Yanase T, Morinaga H, et al. Atrazine-induced aromataseexpression is SF-1dependent: implications for endocrinedisruption in wildlife and reproductive cancers in humans[J].Environ Health Perspect.2007,115(5):720-727.
[74] Hayes T B, Khoury V, Narayan A, et al. Atrazine induces completefeminization and chemical castration in male African clawed frogs(Xenopus laevis)[J]. Proc Natl Acad Sci U S A.2010,107(10):4612-4617.
[75] Fan W, Yanase T, Morinaga H, et al. Herbicide atrazine activatesSF-1by direct affinity and concomitant co-activators recruitmentsto induce aromatase expression via promoter II[J]. BiochemBiophys Res Commun.2007,355(4):1012-1018.
[76] Fan W, Yanase T, Morinaga H, et al. Atrazine-induced aromataseexpression is SF-1dependent: implications for endocrinedisruption in wildlife and reproductive cancers in humans[J].Environ Health Perspect.2007,115(5):720-727.
[77] Van Meter R J, Swan C M. Road salts as environmental constraintsin urban pond food webs[J]. PLoS One.2014,9(2): e90168.
[78] Swan W I, Anchondo I M. Ethical selection of enteral and infantformula: demonstrating evidence-based practice and a responsiblevendor relationship[J]. J Acad Nutr Diet.2014,114(3):489-490.
[79] Lin N, Garry V F. In vitro studies of cellular and moleculardevelopmental toxicity of adjuvants, herbicides, and fungicidescommonly used in Red River Valley, Minnesota[J]. J ToxicolEnviron Health A.2000,60(6):423-439.
[80] Shi X, Richard J, Zirbes K M, et al. Cooperative interaction of Etv2and Gata2regulates the development of endothelial andhematopoietic lineages[J]. Dev Biol.2014.
[81] Mills C. One pill makes you smarter: an ethical appraisal of the riseof Ritalin[J]. Rep Inst Philos Public Policy.1998,18(4):13-17.
[82] Mills W J, Whaley R. Frostbite: experience with rapid rewarmingand ultrasonic therapy.1960-1[J]. Wilderness Environ Med.1998,9(4):226-247.
[83] Karrow N A, Guo T L, Delclos K B, et al. Nonylphenol alters theactivity of splenic NK cells and the numbers of leukocytesubpopulations in Sprague-Dawley rats: a two-generation feedingstudy[J]. Toxicology.2004,196(3):237-245.
[84] Munger B S, Whelan G P. Role of the American Board ofEmergency Medicine in the specialty of emergency medicine[J].Ann Emerg Med.1997,30(2):219-223.
[85] Wu T, Schwender H, Ruczinski I, et al. Evidence ofgene-environment interaction for two genes on chromosome4andenvironmental tobacco smoke in controlling the risk ofnonsyndromic cleft palate[J]. PLoS One.2014,9(2): e88088.
[86] Vermeeren A, Vuurman E F, Leufkens T R, et al. Residual Effectsof Low-Dose Sublingual Zolpidem on Highway DrivingPerformance the Morning after Middle-of-the-Night Use[J]. Sleep.2014,37(3):489-496.
[87] van Leeuwen J M.[Trends in research related to the health ofpigs][J]. Tijdschr Diergeneeskd.1988,113(21):1172-1180.
[88] van Leeuwen A F, Collewijn H, Erkelens C J. Dynamics ofhorizontal vergence movements: interaction with horizontal andvertical saccades and relation with monocular preferences[J].Vision Res.1998,38(24):3943-3954.
[89] Robutti F, Betta P G, Donna A, et al. A morphometrically-basedclassification rule for the diagnosis of primary mesotheliallesions[J]. J Pathol.1990,162(1):57-60.
[90] Snedeker J D, Kaplan S L, Dodge P R, et al. Subdural effusion andits relationship with neurologic sequelae of bacterial meningitis ininfancy: a prospective study[J]. Pediatrics.1990,86(2):163-170.
[91] Sathiakumar N, Delzell E, Morrisey M A, et al. Mortality followingbone metastasis and skeletal-related events among patients65years and above with lung cancer: A population-based analysis ofU.S. Medicare beneficiaries,1999-2006[J]. Lung India.2013,30(1):20-26.
[92] Meng W, Li X, Bai Z, et al. Silencing Alpha-Fetoprotein InhibitsVEGF and MMP-2/9Production in Human HepatocellularCarcinoma Cell[J]. PLoS One.2014,9(2): e90660.
[93] Ou Y R, Kang M, Zhou L.[Infection with L-form of Helicobacterpylori and expressions of MIF, MMP9and VEGF in gastriccarcinoma][J]. Nan Fang Yi Ke Da Xue Xue Bao.2014,34(2):180-187.
[94] Zhang Q W, Gan H Y, Cheng Z N, et al.[2-Deoxy-D-glucosecombined with Taxol inhibits VEGF expression and inducesapoptosis in orthotopically transplanted breast cancer in C3Hmice][J]. Nan Fang Yi Ke Da Xue Xue Bao.2014,34(2):193-196.
[95] Zhang Z L, Zhang J F, Yuan Y F, et al. Suppression of angiogenesisand tumor growth and using an anti-angiopoietin-2single-chainantibody[J]. Exp Ther Med.2014,7(3):543-552.
[96] Tuuminen R, Sahanne S, Loukovaara S. Low intravitrealangiopoietin-2and VEGF levels in vitrectomized diabetic patientswith simvastatin treatment[J]. Acta Ophthalmol.2014.
[97] Zhao Q, Caballero O L, Davis I D, et al. Tumor-specific isoformswitch of the fibroblast growth factor receptor2underlies themesenchymal and malignant phenotypes of clear cell renal cellcarcinomas[J]. Clin Cancer Res.2013,19(9):2460-2472.
[98] Li X, Wang Y, Zhao Y, et al. Immunotherapy of tumor with vaccinebased on basic fibroblast growth factor-activated fibroblasts[J]. JCancer Res Clin Oncol.2014,140(2):271-280.
[99] Salotti J, Dias M H, Koga M M, et al. Fibroblast growth factor2causes G2/M cell cycle arrest in ras-driven tumor cells through aSrc-dependent pathway[J]. PLoS One.2013,8(8): e72582.
[100] Kim J H, Frantz A M, Anderson K L, et al. Interleukin-8promotescanine hemangiosarcoma growth by regulating the tumormicroenvironment[J]. Exp Cell Res.2014.
[101] Nagaoka H, Iino Y, Takei H, et al. Platelet-derived endothelialcell growth factor/thymidine phosphorylase expression inmacrophages correlates with tumor angiogenesis and prognosis ininvasive breast cancer[J]. Int J Oncol.1998,13(3):449-454.
[102] Zhou J, Tang Z Y, Fan J, et al. Expression of platelet-derivedendothelial cell growth factor and vascular endothelial growthfactor in hepatocellular carcinoma and portal vein tumorthrombus[J]. J Cancer Res Clin Oncol.2000,126(1):57-61.
[103] Miszczak-Zaborska E, Smolarek M, Bartkowiak J.[Influence ofthe thymidine phosphorylase (platelet-derived endothelial cellgrowth factor) on tumor angiogenesis. Catalytic activity of enzymeinhibitors][J]. Postepy Biochem.2010,56(1):61-66.
[104] Martin M D, Matrisian L M. The other side of MMPs: protectiveroles in tumor progression[J]. Cancer Metastasis Rev.2007,26(3-4):717-724.
[105] Xiong T, Peng H, Chen G, et al. The expression and activity ofMMPs are increased in residual tumor tissues after the terminationof immunotherapy[J]. J Huazhong Univ Sci Technolog Med Sci.2008,28(4):375-378.
[106] Bourboulia D, Stetler-Stevenson W G. Matrix metalloproteinases(MMPs) and tissue inhibitors of metalloproteinases (TIMPs):Positive and negative regulators in tumor cell adhesion[J]. SeminCancer Biol.2010,20(3):161-168.
[107] Lukaszewicz-Zajac M, Mroczko B, Kornhuber J, et al. Matrixmetalloproteinases (MMPs) and their tissue inhibitors (TIMPs) inthe tumors of central nervous system (CNS)[J]. J Neural Transm.2013.
[108] Ribeiro B F, Iglesias D P, Nascimento G J, et al.Immunoexpression of MMPs-1,-2, and-9in ameloblastoma andodontogenic adenomatoid tumor[J]. Oral Dis.2009,15(7):472-477.
[109] Tian M, Wan Y, Tang J, et al. Depletion of tissue factorsuppresses hepatic metastasis and tumor growth in colorectalcancer via the downregulation of MMPs and the induction ofautophagy and apoptosis[J]. Cancer Biol Ther.2011,12(10):896-907.
[110] Nakamura T, Fukui M, Ebihara I, et al. Effects of low-protein dieton mRNA for ECM components, MMPs and TIMPs in glomeruli offocal glomerular sclerosis[J]. Contrib Nephrol.1994,107:146-155.
[111] Wang L, Xu Y X, Du XJ, et al. Dynamic expression profiles ofMMPs/TIMPs and collagen deposition in mechanically unloadedrat heart: implications for left ventricular assist devicesupport-induced cardiac alterations[J]. J Physiol Biochem.2013,69(3):477-485.
[112] Hassan Z K, Daghestani M H. Curcumin effect on MMPs andTIMPs genes in a breast cancer cell line[J]. Asian Pac J CancerPrev.2012,13(7):3259-3264.
[113] Meng W, Li X, Bai Z, et al. Silencing Alpha-Fetoprotein InhibitsVEGF and MMP-2/9Production in Human HepatocellularCarcinoma Cell[J]. PLoS One.2014,9(2): e90660.
[114] Fiorentini C, Bodei S, Bedussi F, et al. GPNMB/OA PROTEININCREASES THE INVASIVENESS OF HUMAN METASTATICPROSTATE CANCER CELL LINES DU145AND PC3THROUGHMMP-2AND MMP-9ACTIVITY[J]. Exp Cell Res.2014.
[115] Entschladen F, Zanker K S, Powe D G. Heterotrimeric G proteinsignaling in cancer cells with regard to metastasis formation[J].Cell Cycle.2011,10(7):1086-1091.
[116] Zhou Y, Guan X, Yu M, et al. Angiogenic/osteogenic response ofBMMSCs on bone-derived scaffold: Effect of hypoxia and role ofPI3K/Akt-mediated VEGF-VEGFR pathway[J]. Biotechnol J.2014.
[117] Mei J, Zhu X, Wang Z, et al. VEGFR, RET, and RAF/MEK/ERKPathway Take Part in the Inhibition of Osteosarcoma MG63Cellswith Sorafenib Treatment[J]. Cell Biochem Biophys.2013.
[118] Lin H C, Huang Y T, Yang Y Y, et al. Beneficial effects of dualVEGFR/FGFR inhibitor brivanib alaninate in cirrhotic portalhypertensive rats[J]. J Gastroenterol Hepatol.2013.
[119] Jin K, Li G, Cui B, et al. Assessment of a novel VEGF targetedagent using patient-derived tumor tissue xenograft models of coloncarcinoma with lymphatic and hepatic metastases[J]. PLoS One.2011,6(12): e28384.
[120] Moon J I, Kim J M, Jung G O, et al.[Expression of vascularendothelial growth factor (VEGF) family members and prognosisafter hepatic resection in HBV-related hepatocellularcarcinoma][J]. Korean J Hepatol.2008,14(2):185-196.
[121] Li H J, Wang J M, Tian Y T, et al.[Effect of matrine on Fas,VEGF, and activities of telomerase of MCF-7cells][J]. ZhongguoZhong Xi Yi Jie He Za Zhi.2013,33(9):1247-1251.
[122] Zhang Q W, Gan H Y, Cheng Z N, et al.[2-Deoxy-D-glucosecombined with Taxol inhibits VEGF expression and inducesapoptosis in orthotopically transplanted breast cancer in C3Hmice][J]. Nan Fang Yi Ke Da Xue Xue Bao.2014,34(2):193-196.
[123] Tseng P L, Tai M H, Huang C C, et al. Overexpression of VEGF isassociated with positive p53immunostaining in hepatocellularcarcinoma (HCC) and adverse outcome of HCC patients[J]. J SurgOncol.2008,98(5):349-357.
[124] Kim J H, Choi K Y, Lee D J, et al. Loss of Heterozygosities inFive Tumor Suppressor Genes (FHIT Gene, p16, pRb, E-Cadherinand p53) in Thyroid Tumors[J]. Clin Exp Otorhinolaryngol.2014,7(1):53-58.
[125] Feinmesser M, Halpern M, Fenig E, et al. Expression of theapoptosis-related oncogenes bcl-2, bax, and p53in Merkel cellcarcinoma: can they predict treatment response and clinicaloutcome?[J]. Hum Pathol.1999,30(11):1367-1372.
[126] Wang W, Johansson H, Bergholm U, et al. Apoptosis andExpression of the Proto-Oncogenes bcl-2and p53and theProliferation Factor Ki-67in Human Medullary ThyroidCarcinoma[J]. Endocr Pathol.1996,7(1):37-45.
[127] Sathornsumetee S, Desjardins A, Vredenburgh J J, et al. Phase IItrial of bevacizumab and erlotinib in patients with recurrentmalignant glioma[J]. Neuro Oncol.2010,12(12):1300-1310.
[128] Herbst R S, Johnson D H, Mininberg E, et al. Phase I/II trialevaluating the anti-vascular endothelial growth factor monoclonalantibody bevacizumab in combination with the HER-1/epidermalgrowth factor receptor tyrosine kinase inhibitor erlotinib forpatients with recurrent non-small-cell lung cancer[J]. J Clin Oncol.2005,23(11):2544-2555.
[129] Wen P Y, Chang S M, Lamborn K R, et al. Phase I/II study oferlotinib and temsirolimus for patients with recurrent malignantgliomas: North American Brain Tumor Consortium trial04-02[J].Neuro Oncol.2014.
[130] Fletcher S, Drewry J A, Shahani V M, et al. Molecular disruptionof oncogenic signal transducer and activator of transcription3(STAT3) protein[J]. Biochem Cell Biol.2009,87(6):825-833.
[131] Wheeler S E, Suzuki S, Thomas S M, et al. Epidermal growthfactor receptor variant III mediates head and neck cancer cellinvasion via STAT3activation[J]. Oncogene.2010,29(37):5135-5145.
[132] Huang C, Yang G, Jiang T, et al. Effects of IL-6and AG490onregulation of Stat3signaling pathway and invasion of humanpancreatic cancer cells in vitro[J]. J Exp Clin Cancer Res.2010,29:51.
[133] Ng D C, Lim C P, Lin B H, et al. SCG10-like protein (SCLIP) is aSTAT3-interacting protein involved in maintaining epithelialmorphology in MCF-7breast cancer cells[J]. Biochem J.2010,425(1):95-105.
[134] Rivat C, Rodrigues S, Bruyneel E, et al. Implication of STAT3signaling in human colonic cancer cells during intestinal trefoilfactor3(TFF3)--and vascular endothelial growth factor-mediatedcellular invasion and tumor growth[J]. Cancer Res.2005,65(1):195-202.
[135] Cascio S, D'Andrea A, Ferla R, et al. miR-20b modulates VEGFexpression by targeting HIF-1alpha and STAT3in MCF-7breastcancer cells[J]. J Cell Physiol.2010,224(1):242-249.
[136] Cheng G Z, Zhang W Z, Sun M, et al. Twist is transcriptionallyinduced by activation of STAT3and mediates STAT3oncogenicfunction[J]. J Biol Chem.2008,283(21):14665-14673.
[137] Bhardwaj A, Sethi G, Vadhan-Raj S, et al. Resveratrol inhibitsproliferation, induces apoptosis, and overcomes chemoresistancethrough down-regulation of STAT3and nuclearfactor-kappaB-regulated antiapoptotic and cell survival geneproducts in human multiple myeloma cells[J]. Blood.2007,109(6):2293-2302.
[138] Otero D C, Poli V, David M, et al. Cutting edge: inherent andacquired resistance to radiation-induced apoptosis in B cells: apivotal role for STAT3[J]. J Immunol.2006,177(10):6593-6597.
[139] Kim K W, Mutter R W, Cao C, et al. Inhibition of signaltransducer and activator of transcription3activity results indown-regulation of Survivin following irradiation[J]. Mol CancerTher.2006,5(11):2659-2665.
[140] Caldera V, Mellai M, Annovazzi L, et al. Stat3expression and itscorrelation with proliferation and apoptosis/autophagy ingliomas[J]. J Oncol.2008,2008:219241.
[141] Liu H J, Moroi Y, Masuda T, et al. Expression of phosphorylatedStat3, cyclin D1and Bcl-xL in extramammary Paget disease[J]. BrJ Dermatol.2006,154(5):926-932.
[142] Turkson J. STAT proteins as novel targets for cancer drugdiscovery[J]. Expert Opin Ther Targets.2004,8(5):409-422.
[143] Liang Q, Ma C, Zhao Y, et al. Inhibition of STAT3reducesastrocytoma cell invasion and constitutive activation of STAT3predicts poor prognosis in human astrocytoma[J]. PLoS One.2013,8(12): e84723.
[144] Xiong H, Du W, Wang J L, et al. Constitutive activation of STAT3is predictive of poor prognosis in human gastric cancer[J]. J MolMed (Berl).2012,90(9):1037-1046.
[145] Niu G, Bowman T, Huang M, et al. Roles of activated Src andStat3signaling in melanoma tumor cell growth[J]. Oncogene.2002,21(46):7001-7010.
[146] Baran-Marszak F, Boukhiar M, Harel S, et al. Constitutive andB-cell receptor-induced activation of STAT3are importantsignaling pathways targeted by bortezomib in leukemic mantle celllymphoma[J]. Haematologica.2010,95(11):1865-1872.
[147] Chung S S, Aroh C, Vadgama J V. Constitutive activation ofSTAT3signaling regulates hTERT and promotes stem cell-liketraits in human breast cancer cells[J]. PLoS One.2013,8(12):e83971.
[148] Grandis J R, Drenning S D, Zeng Q, et al. Constitutive activationof Stat3signaling abrogates apoptosis in squamous cellcarcinogenesis in vivo[J]. Proc Natl Acad Sci U S A.2000,97(8):4227-4232.
[149] Gao B, Shen X, Kunos G, et al. Constitutive activation ofJAK-STAT3signaling by BRCA1in human prostate cancercells[J]. FEBS Lett.2001,488(3):179-184.
[150] Wang Y, Ren X, Deng C, et al. Mechanism of the inhibition of theSTAT3signaling pathway by EGCG[J]. Oncol Rep.2013,30(6):2691-2696.
[151] Keasey M P, Kang S S, Lovins C, et al. Inhibition of a novelspecific neuroglial integrin signaling pathway increasesSTAT3-mediated CNTF expression[J]. Cell Commun Signal.2013,11(1):35.
[152] Seo C R, Yang D K, Song N J, et al. Cucurbitacin B andcucurbitacin I suppress adipocyte differentiation through inhibitionof STAT3signaling[J]. Food Chem Toxicol.2014,64:217-224.
[153] Kijima T, Niwa H, Steinman R A, et al. STAT3activationabrogates growth factor dependence and contributes to head andneck squamous cell carcinoma tumor growth in vivo[J]. CellGrowth Differ.2002,13(8):355-362.
[154] Fantin V R, Loboda A, Paweletz C P, et al. Constitutive activationof signal transducers and activators of transcription predictsvorinostat resistance in cutaneous T-cell lymphoma[J]. Cancer Res.2008,68(10):3785-3794.
[155] Woo S, Lee B L, Yoon J, et al. Constitutive activation of signaltransducers and activators of transcription3correlates with betterprognosis, cell proliferation and hypoxia-inducible factor-1alphain human gastric cancer[J]. Pathobiology.2011,78(6):295-301.
[156] Ishii H, Hulett M D, Li J M, et al. Yin Yang-1inhibits tumor cellgrowth and inhibits p21WAF1/Cip1complex formation with cdk4and cyclin D1[J]. Int J Oncol.2012,40(5):1575-1580.
[157] Lin D C, Shi Z Z, Xue L Y, et al.[Expression of cell cycle relatedproteins cyclin D1, p53and p21WAF1/Cip1in esophagealsquamous cell carcinoma][J]. Yi Chuan.2010,32(5):455-460.
[158] Dang C V. c-Myc target genes involved in cell growth, apoptosis,and metabolism[J]. Mol Cell Biol.1999,19(1):1-11.
[159] Prendergast G C. Mechanisms of apoptosis by c-Myc[J].Oncogene.1999,18(19):2967-2987.
[160] Sakamuro D, Eviner V, Elliott K J, et al. c-Myc induces apoptosisin epithelial cells by both p53-dependent and p53-independentmechanisms[J]. Oncogene.1995,11(11):2411-2418.
[161] Sellier H, Rebillard A, Guette C, et al. How should we defineSTAT3as an oncogene and as a potential target for therapy?[J].JAKSTAT.2013,2(3): e24716.
[162] Kijima T, Niwa H, Steinman R A, et al. STAT3activationabrogates growth factor dependence and contributes to head andneck squamous cell carcinoma tumor growth in vivo[J]. CellGrowth Differ.2002,13(8):355-362.
[163] Vogelstein B, Lane D, Levine A J. Surfing the p53network[J].Nature.2000,408(6810):307-310.
[164] Raman V, Martensen S A, Reisman D, et al. CompromisedHOXA5function can limit p53expression in human breasttumours[J]. Nature.2000,405(6789):974-978.
[165] Yu H, Jove R. The STATs of cancer--new molecular targets comeof age[J]. Nat Rev Cancer.2004,4(2):97-105.
[166] Folkman J. What is the evidence that tumors are angiogenesisdependent?[J]. J Natl Cancer Inst.1990,82(1):4-6.
[167] Hanahan D, Folkman J. Patterns and emerging mechanisms of theangiogenic switch during tumorigenesis[J]. Cell.1996,86(3):353-364.
[168] Rak J, Yu J L, Klement G, et al. Oncogenes and angiogenesis:signaling three-dimensional tumor growth[J]. J Investig DermatolSymp Proc.2000,5(1):24-33.
[169] Grunstein J, Roberts W G, Mathieu-Costello O, et al.Tumor-derived expression of vascular endothelial growth factor isa critical factor in tumor expansion and vascular function[J].Cancer Res.1999,59(7):1592-1598.
[170] Chakrabarti M, Banik N L, Ray S K. Photofrin basedphotodynamic therapy and miR-99a transfection inhibited FGFR3and PI3K/Akt signaling mechanisms to control growth of humanglioblastoma In vitro and in vivo[J]. PLoS One.2013,8(2):e55652.
[171] Millauer B, Shawver L K, Plate K H, et al. Glioblastoma growthinhibited in vivo by a dominant-negative Flk-1mutant[J]. Nature.1994,367(6463):576-579.
[172] Lohela M, Bry M, Tammela T, et al. VEGFs and receptorsinvolved in angiogenesis versus lymphangiogenesis[J]. Curr OpinCell Biol.2009,21(2):154-165.
[173] Wietecha M S, Dipietro L A. Therapeutic Approaches to theRegulation of Wound Angiogenesis[J]. Adv Wound Care (NewRochelle).2013,2(3):81-86.
[174] Zhou W, Wang G, Guo S. Regulation of angiogenesis via Notchsignaling in breast cancer and cancer stem cells[J]. BiochimBiophys Acta.2013,1836(2):304-320.
[175] Plein A, Fantin A, Ruhrberg C. Neuropilin regulation ofangiogenesis, arteriogenesis and vascular permeability[J].Microcirculation.2014.
[176] Jo D H, Kim J H, Kim K W, et al. Allosteric regulation ofpathologic angiogenesis: potential application forangiogenesis-related blindness[J]. Arch Pharm Res.2014,37(3):285-298.
[177] Niu G, Wright K L, Huang M, et al. Constitutive Stat3activityup-regulates VEGF expression and tumor angiogenesis[J].Oncogene.2002,21(13):2000-2008.
[178] Wei L H, Kuo M L, Chen C A, et al. Interleukin-6promotescervical tumor growth by VEGF-dependent angiogenesis via aSTAT3pathway[J]. Oncogene.2003,22(10):1517-1527.
[179] Bartoli M, Platt D, Lemtalsi T, et al. VEGF differentiallyactivates STAT3in microvascular endothelial cells[J]. FASEB J.2003,17(11):1562-1564.
[180] Ohotski J, Rosen H, Bittman R, et al. Sphingosine kinase2prevents the nuclear translocation of sphingosine1-phosphatereceptor-2and tyrosine416phosphorylated c-Src and increasesestrogen receptor negative MDA-MB-231breast cancer cell growth:The role of sphingosine1-phosphate receptor-4[J]. Cell Signal.2014,26(5):1040-1047.
[181] Yahata Y, Shirakata Y, Tokumaru S, et al. Nuclear translocationof phosphorylated STAT3is essential for vascular endothelialgrowth factor-induced human dermal microvascular endothelialcell migration and tube formation[J]. J Biol Chem.2003,278(41):40026-40031.
[182] Gong A, Zhang Z, Xiao D, et al. Localization of phosphorylatedTrkA in carrier vesicles involved in its nuclear translocation inU251cell line[J]. Sci China C Life Sci.2007,50(2):141-146.
[183] Deo D D, Axelrad T W, Robert E G, et al. Phosphorylation ofSTAT-3in response to basic fibroblast growth factor occursthrough a mechanism involving platelet-activating factor, JAK-2,and Src in human umbilical vein endothelial cells. Evidence for adual kinase mechanism[J]. J Biol Chem.2002,277(24):21237-21245.
[184] Holloway A C, Anger D A, Crankshaw D J, et al.Atrazine-induced changes in aromatase activity in estrogensensitive target tissues[J]. J Appl Toxicol.2008,28(3):260-270.
[185] Holloway A C, Anger D A, Crankshaw D J, et al.Atrazine-induced changes in aromatase activity in estrogensensitive target tissues[J]. J Appl Toxicol.2008,28(3):260-270.
[186] Grun F, Blumberg B. Perturbed nuclear receptor signaling byenvironmental obesogens as emerging factors in the obesitycrisis[J]. Rev Endocr Metab Disord.2007,8(2):161-171.
[187] Bays H, Blonde L, Rosenson R. Adiposopathy: how do diet,exercise and weight loss drug therapies improve metabolic diseasein overweight patients?[J]. Expert Rev Cardiovasc Ther.2006,4(6):871-895.
[188] Williams G. Aromatase up-regulation, insulin and raisedintracellular oestrogens in men, induce adiposity, metabolicsyndrome and prostate disease, via aberrant ER-alpha and GPERsignalling[J]. Mol Cell Endocrinol.2012,351(2):269-278.
[189] Mccauley L K, Tozum T F, Kozloff K M, et al. Transgenic modelsof metabolic bone disease: impact of estrogen receptor deficiencyon skeletal metabolism[J]. Connect Tissue Res.2003,44Suppl1:250-263.
[190] Hsia J, Bittner V, Tripputi M, et al. Metabolic syndrome andcoronary angiographic disease progression: the Women'sAngiographic Vitamin&Estrogen trial[J]. Am Heart J.2003,146(3):439-445.
[191] Lavranos G, Nikolaou A, Angelopoulou R. Octreotide inhibitsliver regeneration by suppressing regional estrogen receptor typea expression[J]. Hell J Nucl Med.2014,17Suppl1:56-61.
[192] de Vries H A, Ponds F A, Nieuwenhuijs V B, et al. Evidence thatestrogen receptors play a limited role in mediating enhancedrecovery of bile flow in female rats in the acute phase of liverischemia reperfusion injury[J]. Ann Hepatol.2013,12(1):130-137.
[193] Pedram A, Razandi M, O'Mahony F, et al. Estrogen reduces lipidcontent in the liver exclusively from membrane receptorsignaling[J]. Sci Signal.2013,6(276): a36.
[194] Zhang B, Wu Z Y. Estrogen derivatives: novel therapeutic agentsfor liver cirrhosis and portal hypertension[J]. Eur J GastroenterolHepatol.2013,25(3):263-270.
[195] Ahmed M A, Hassanein K M. Effects of estrogen onhyperglycemia and liver dysfunction in diabetic male rats[J]. Int JPhysiol Pathophysiol Pharmacol.2012,4(3):156-166.
[196] Humble J L, Saaristo M, Lindstrom K, et al. Effects of17alpha-ethinyl estradiol exposure on estrogen receptors alpha andbeta and vitellogenins A, B and C mRNA expression in the liver ofsand goby (Pomatoschistus minutus)[J]. Mar Environ Res.2014.
[197] Oberley T D, Oberley L W, Slattery A F, et al.Immunohistochemical localization of glutathione-S-transferase andglutathione peroxidase in adult Syrian hamster tissues and duringkidney development[J]. Am J Pathol.1991,139(2):355-369.
[198] Oberley T D, Slattery A F, Gonzalez A, et al. Comparativemorphologic and immunohistochemical studies of estrogen plusalpha-naphthoflavone-induced liver tumors in Syrian hamsters andrats[J]. Am J Pathol.1991,139(3):669-679.
[199] Ueda M, Imai T, Takizawa T, et al. Possible enhancing effects ofatrazine on growth of7,12-dimethylbenz(a) anthracene-inducedmammary tumors in ovariectomized Sprague-Dawley rats[J].Cancer Sci.2005,96(1):19-25.
[200] Albanito L, Lappano R, Madeo A, et al. Retraction:G-Protein-Coupled Receptor30and Estrogen Receptor-alpha AreInvolved in the Proliferative Effects Induced by Atrazine inOvarian Cancer Cells[J]. Environ Health Perspect.2014,122(2):A42.
[201] Albanito L, Lappano R, Madeo A, et al. G-protein-coupledreceptor30and estrogen receptor-alpha are involved in theproliferative effects induced by atrazine in ovarian cancer cells[J].Environ Health Perspect.2008,116(12):1648-1655.
[202] Adesiyan A C, Oyejola T O, Abarikwu S O, et al. Seleniumprovides protection to the liver but not the reproductive organs inan atrazine-model of experimental toxicity[J]. Exp Toxicol Pathol.2011,63(3):201-207.
[203] Kmetic I, Gaurina S V, Slivac I, et al. Atrazine exposuredecreases cell proliferation in Chinese Hamster Ovary (CHO-K1)cell line[J]. Bull Environ Contam Toxicol.2008,81(2):205-209.
[204] Velinov N, Poptodorov G, Gabrovski N, et al.[The role ofmatrixmetalloproteinases in the tumor growth and metastasis][J].Khirurgiia (Sofiia).2010(1):44-49.
[205] Albanito L, Lappano R, Madeo A, et al. Retraction:G-Protein-Coupled Receptor30and Estrogen Receptor-alpha AreInvolved in the Proliferative Effects Induced by Atrazine inOvarian Cancer Cells[J]. Environ Health Perspect.2014,122(2):A42.
[206] Albanito L, Lappano R, Madeo A, et al. G-protein-coupledreceptor30and estrogen receptor-alpha are involved in theproliferative effects induced by atrazine in ovarian cancer cells[J].Environ Health Perspect.2008,116(12):1648-1655.
[207] Sathiakumar N, Maclennan P A, Mandel J, et al. A review ofepidemiologic studies of triazine herbicides and cancer[J]. Crit RevToxicol.2011,41Suppl1:1-34.
[208] Sathiakumar N, Delzell E. A review of epidemiologic studies oftriazine herbicides and cancer[J]. Crit Rev Toxicol.1997,27(6):599-612.
[209] Inoue K, Torimura T, Nakamura T, et al. Vandetanib, an inhibitorof VEGF receptor-2and EGF receptor, suppresses tumordevelopment and improves prognosis of liver cancer in mice[J].Clin Cancer Res.2012,18(14):3924-3933.
[210] Bertin S, Mohsen-Kanson T, Baque P, et al. Tumormicroenvironment modifications induced by soluble VEGFreceptor expression in a rat liver metastasis model[J]. CancerLett.2010,298(2):264-272.
[211] Guo W J, Li J, Chen Z, et al. Transient increased expression ofVEGF and MMP-1in a rat liver tumor model after hepatic arterialocclusion[J]. Hepatogastroenterology.2004,51(56):381-386.
[212] Mukozu T, Nagai H, Matsui D, et al. Serum VEGF as a tumormarker in patients with HCV-related liver cirrhosis andhepatocellular carcinoma[J]. Anticancer Res.2013,33(3):1013-1021.
[213] Basappa, Ananda K C, Nanjunda S S, et al. Anti-tumor andanti-angiogenic activity of novel hydantoin derivatives: Inhibitionof VEGF secretion in liver metastatic osteosarcoma cells[J].Bioorg Med Chem.2009,17(14):4928-4934.
[214] Alavanja M C, Hoppin J A, Kamel F. Health effects of chronicpesticide exposure: cancer and neurotoxicity[J]. Annu Rev PublicHealth.2004,25:155-197.
[215] Jaga K, Dharmani C. The epidemiology of pesticide exposure andcancer: A review[J]. Rev Environ Health.2005,20(1):15-38.
[216] Wesseling C, Mcconnell R, Partanen T, et al. Agriculturalpesticide use in developing countries: health effects and researchneeds[J]. Int J Health Serv.1997,27(2):273-308.
[217] Moser G J, Meyer S A, Smart R C. The chlorinated pesticidemirex is a novel nonphorbol ester-type tumor promoter in mouseskin[J]. Cancer Res.1992,52(3):631-636.
[218] Murali M E, Rajaran G M, Amirtha G D, et al. Elucidation oftumor-promoting potential of a combination pesticide byshort-term, in vivo bioassay[J]. J Environ Pathol Toxicol Oncol.2001,20(3):229-236.
[219] Ouyang Y H, Li S L, Song W, et al.[Effect of penehyclidinehydrochloride on tumor necrosis factor-alpha in liver and spleen inmice with acute organophosphorus pesticide poisoning][J].Zhongguo Wei Zhong Bing Ji Jiu Yi Xue.2010,22(4):238-239.
[220] Pang L, Close M, Flintoft M. Degradation and sorption of atrazine,hexazinone and procymidone in coastal sand aquifer media[J].Pest Manag Sci.2005,61(2):133-143.
[221] Zeljezic D, Garaj-Vrhovac V. Genotoxicity evaluation ofpesticide formulations containing alachlor and atrazine in multiplemouse tissues (blood, kidney, liver, bone marrow, spleen) by cometassay[J]. Neoplasma.2004,51(3):198-203.
[222] Simpkins J W, Swenberg J A, Weiss N, et al. Atrazine and breastcancer: a framework assessment of the toxicological andepidemiological evidence[J]. Toxicol Sci.2011,123(2):441-459.
[223] Rajkovic V, Kovac R, Koledin I, et al. Atrazine-induced changesin the myocardial structure of peripubertal rats[J]. Toxicol IndHealth.2012.
[224] Holloway A C, Anger D A, Crankshaw D J, et al.Atrazine-induced changes in aromatase activity in estrogensensitive target tissues[J]. J Appl Toxicol.2008,28(3):260-270.
[225] Wincewicz A, Baltaziak M, Kanczuga-Koda L, et al. STAT3andapoptosis regulators: Bak and Bcl-xL in endometrioidadenocarcinomas of different estrogen receptor-alphaimmunoprofile[J]. Gynecol Endocrinol.2011,27(8):536-540.
[226] Mitra R, Guo Z, Milani M, et al. CYP3A4mediates growth ofestrogen receptor-positive breast cancer cells in part by inducingnuclear translocation of phospho-Stat3through biosynthesis of(+/-)-14,15-epoxyeicosatrienoic acid (EET)[J]. J Biol Chem.2011,286(20):17543-17559.
[227] Gao Q, Mezei G, Nie Y, et al. Anorectic estrogen mimics leptin'seffect on the rewiring of melanocortin cells and Stat3signaling inobese animals[J]. Nat Med.2007,13(1):89-94.
[228] Wang L H, Yang X Y, Mihalic K, et al. Activation of estrogenreceptor blocks interleukin-6-inducible cell growth of humanmultiple myeloma involving molecular cross-talk between estrogenreceptor and STAT3mediated by co-regulator PIAS3[J]. J BiolChem.2001,276(34):31839-31844.
[229] Zahid M, Beseler C L, Hall J B, et al. Unbalanced estrogenmetabolism in ovarian cancer[J]. Int J Cancer.2013.
[230] Fuente-Martin E, Garcia-Caceres C, Morselli E, et al. Estrogen,astrocytes and the neuroendocrine control of metabolism[J]. RevEndocr Metab Disord.2013,14(4):331-338.
[231] Sharma K L, Agarwal A, Misra S, et al. Association of geneticvariants of xenobiotic and estrogen metabolism pathway (CYP1A1and CYP1B1) with gallbladder cancer susceptibility[J]. TumourBiol.2014.
[232] Fortner R T, Oh H, Daugherty S E, et al. Analgesic Use andPatterns of Estrogen Metabolism in Premenopausal Women[J].Horm Cancer.2014.
[233] Demaria M, Camporeale A, Poli V. STAT3and metabolism: Howmany ways to use a single molecule?[J]. Int J Cancer.2014.
[234] Kinoshita S, Ogawa W, Okamoto Y, et al. Role of hepatic STAT3in the regulation of lipid metabolism[J]. Kobe J Med Sci.2008,54(4): E200-E208.
[235] Liu J, Jing X, Gan L, et al. The JAK2/STAT3signal pathwayregulates the expression of genes related to skeletal muscledevelopment and energy metabolism in mice and mouse skeletalmuscle cells[J]. Biosci Biotechnol Biochem.2012,76(10):1866-1870.
[236] Bravard A, Vial G, Chauvin M A, et al. FTO contributes to hepaticmetabolism regulation through regulation of leptin action andSTAT3signalling in liver[J]. Cell Commun Signal.2014,12:4.
[237] Jowa L, Howd R. Should atrazine and related chlorotriazines beconsidered carcinogenic for human health risk assessment?[J]. JEnviron Sci Health C Environ Carcinog Ecotoxicol Rev.2011,29(2):91-144.