PGE_2-EP_1信号转导通路在肝细胞癌中的作用及表没食子儿茶素没食子酸酯对其的影响
|
摘要
肝细胞癌(hepatocellular carcinoma, HCC)在常见的恶性肿瘤中居于第五位，是第三大肿瘤死亡原因。我国每年HCC的发病率约占世界55％，HCC已成为我国第二位恶性肿瘤致死原因。由于HCC发病机制尚不清楚，目前抗肿瘤药物不良反应大，临床上迫切需要寻找高效、低毒的有效物质来抑制HCC细胞侵袭和转移，从而给予更好的干预。在培养的HCC细胞和人HCC组织中COX-2的表达与Akt磷酸化正相关。体内外实验表明，COX-2参与了抑制caspases3和caspases9的活性、降低p53和Bax的表达、增强Akt的活性，可能有抑制肝细胞的调亡的作用。这些现象提示COX-2的表达与肿瘤的发生、发展有着密切关系。而PGE_2作为COX-2的催化产物，在HCC中的水平随着COX-2水平的升高而升高。已知PGE_2通过激活细胞表面的PGE_2受体(prostaglandin E receptor, EP)，与不同的G蛋白偶联，启动下游信号通路而发挥其对细胞功能的调节作用。研究发现，在HCC中EP_1的表达最为丰富。表没食子儿茶素没食子酸酯((-)-Epigallocatechin-3-gallate, EGCG)是绿茶或一些天然药物中的活性成分，具有抑制肿瘤细胞增殖的活性。EGCG具有较强的抗氧化活性，能够保护细胞和DNA免受损害，并有抗辐射和紫外线等生物学功能。近年来，大量实验证明EGCG能干扰癌细胞生存所需的信号传递，如EGCG能与Bcl-2、Bcl-xL的疏水域紧密地结合，有效抑制抗凋亡Bcl-2家族成员，促进肿瘤细胞凋亡。EGCG降低某些致癌物质的活力、提高癌细胞对化疗的敏感性等作用。结合以上背景资料，探讨PGE_2/EP_1信号通路在HCC发展中的作用和EGCG对其的影响，寻求HCC治疗新靶点以及为EGCG用于HCC的治疗提供实验依据。
目的：
观察HCC患者血清中PGE_2水平及EP_1在HCC细胞和人肝细胞中的表达，分析PGE_2及EP_1激动剂ONO-DI-004对HCC增殖和移行的相关性，研究EGCG对PGE_2或ONO-DI-004刺激的HCC的抑制作用及对HCC细胞周期、凋亡、PGE_2、EP_1和Bcl-2表达的影响，初步探讨EGCG抗HCC的作用靶点和机制。
方法：
HepG2细胞设置组别为：对照组、PGE_2(0,4,40,400,4000,40000nM)组、EGCG (12.5,25,50,100μg/mL)组、PGE_2(4,40,400,4000)+EGCG(100μg/mL)组、ONO-DI-004(4,40,400,4000nM)组、ONO-DI-004+EGCG(100μg/mL)组、ONO-8711(210nM,1,5,10μM)组。MTT法检测HepG2的增殖；细胞划痕实验和Transwell侵袭实验检测HepG2的移行；Western blot assay和免疫荧光实验检测HepG2中EP_1、Gq和Bcl-2蛋白的表达；酶联免疫分析法检测HCC患者血清PGE_2及HepG2产生PGE_2和VEGF的水平；流式细胞技术检测HepG2细胞周期和凋亡。
结果：
1. HCC患者的血清中PGE_2的水平呈高表达与正常志愿者血清中的PGE_2水平比较，HCC患者的血浆中PGE_2的水平呈高表达。
2.降低PGE_2和VEGF水平、下调EP_1和Bcl-2的表达是EGCG抑制HCC的重要作用与对照组相比，EGCG (12.5,25,50,100μg/mL)显著降低HepG2中PGE_2和VEGF水平。EP_1在肝癌细胞株MHCC-97L和HepG2中的表达明显高于在人肝细胞株L02中的表达。EGCG (100μg/ml)能显著抑制EP_1受体以及ONO-DI-004诱导的Bcl-2的表达(**P<0.01)。
3. EGCG对外源性PGE_2或ONO-DI-004刺激HCC增殖和移行具有显著的抑制作用
观察EGCG (12.5,25,50,100μg/mL)作用于HepG2后对细胞的增殖作用，100μg/mL EGCG对HepG2作用24h后可显著抑制HepG2的生长(**P<0.01),细胞的平均抑制率为41%。24h的药物浓度与抑制率具有相关性(r=0.8，P=0.02)。EGCG对HepG2具有显著抑制作用。细胞划痕实验和Transwell侵袭实验观察PGE_2(4μM)和ONO-DI-004(400nM)刺激后，HepG2移行较对照组明显增加，EGCG和ONO-8711均能显著抑制HepG2移行，且给予EGCG (100μg/mL)后可显著降低PGE_2和ONO-DI-004刺激的HepG2的移行(**P<0.01)。
4. EGCG能促进HepG2凋亡
流式细胞术检测细胞凋亡率，HepG2经ONO-DI-004(400nM)、PGE_2(4μM)、EGCG (100μg/mL)、EGCG (100μg/mL)+ONO-DI-004(400nM)以及EGCG (100μg/mL)+PGE_2(4μM)作用24h，对照组的细胞凋亡率为(2.36±2.51)%, EGCG (100μg/mL)处理组的凋亡率为(16.8±1.73)%，EGCG (100μg/mL)处理组与对照组的细胞凋亡率相比差异性显著(**P<0.01)。ONO-DI-004(400nM)处理组的凋亡率为(0.6±1.86)%, EGCG (100μg/mL)+ONO-DI-004(400nM)处理组的凋亡率为(12.25±2.64)%，两组间的差异具有显著性(**P<0.01)。EGCG (100μg/mL)可显著的诱导HepG2细胞的凋亡，对PGE_2、ONO-DI-004刺激的HepG2细胞也有明显的促凋亡作用。
结论
1. HCC患者血清中PGE_2表达异常升高，提示PGE_2在HCC患者中发挥重要作用；
2. HCC细胞株中EP1表达较正常肝细胞异常升高，PGE_2可能通过EP1发挥促HCC作用；
3. EGCG呈浓度依赖性抑制由PGE_2和ONO-DI-004刺激引起的HepG2的增殖和转移，抑制HCC异常增殖、移行、细胞周期，诱导凋亡是EGCG的重要作用；
4. EGCG抑制HepG2产生VEGF和PGE_2，降低EP1及ONO-DI-004刺激的Bcl-2的表达，但对Gq蛋白的表达没有影响，降低PGE_2和VEGF水平、下调EP1和Bcl-2的表达是EGCG抑制HCC增殖和移行、诱导凋亡的重要机制之一。
(Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory ofAnti-inflammatory and Immunopharmacology, Anhui Medical University, Ministryof Education, Anhui Key Laboratory of Research and Development of ChineseMedicine, Engineering Technology Research Center of Anti-inflammatory andImmunodrugs in Anhui Province, Scientific and Technological Team ofAnti-inflammatory and Immunopharmacology of Chinese Medicine in AnhuiProvince, the115industial innovation team of basic and applied research intoanti-inflammation and immunodrugs in anhui province, Hefei,230032)
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the thirdmost common cause of death from cancer worldwide. In China HCC accounts for55%of all cases worldwide, and is the second leading cause of cancer death. So farthe tumorigenic mechanism of HCC remains undefined. And the antineoplastic agentsoften achieve low antineoplastic activity at the expense of close to unacceptabletoxicity. Therefore， there is a tremendous interest and urgency to search forrecurrence/metastasis related biomarkers and new agents with high effectiveness andlow toxicity for inhibiting HCC invasion and metastasis, which would better providenovel measures for intervention. The study found that the well-differentiated HCCexpressed COX-2more frequently and strongly than less-differentiated HCC,indicating that COX-2may participate in the early onset of HCC process. The level ofCOX-2expression and Akt phosphorylation was correlated positively in culturedHCC cells and human liver cancer tissues. In vitro and in vivo experiments showedthat COX-2inhibited the activity of caspases3, and caspases9, reduced theexpression of p53and Bax, enhanced Akt activity. COX-2expression was closely
related to HCC occurrence and development. More and more evidences revealed thatCOX-2-derived prostaglandin E2(PGE_2) plays pivotal roles in tumor invasion. InHCC the level of PGE_2was highest compared with other PG productions. PGE_2exertsits biological actions primarily via their respective G protein-coupled receptors(GPCR) superfamily of prostaglandin E receptor (EP). Reports showed that EP_1expression was most abundant in HCC.(-)-epigallocatechin-3-gallate (EGCG) is apolyphenolic compound from tea and natural plants that has been shown to haveanti-tumor activities. However, the delicate mechanisms and signaling pathwaysunderlying the potential anticancer effects of EGCG in HCC cells remain unclear.
This study is designed to investigate the possible mechanism of PGE_2/EP_1signaling pathway in HCC and the effects of EGCG on this signaling. Thus, thesefindings might provide the novel target for HCC treatment and the rationale forEGCG served as a novel therapeutic agent to treat HCC patients, and future study onits clinical application might be worthwhile.
AIMS:
To observe EP1expression in HCC cells and human hepatocyte L02and theserum PGE_2levels of patients with HCC, to analysis of the effects of PGE_2and theEP1agonist ONO-DI-004on proliferation and migration of HCC, to investigate theeffects of EGCG on cell cycle, apoptosis, PGE_2, EP1and Bcl-2expression of HCC, todiscuss the anti-HCC mechanism of EGCG.
METHODS:
HepG2cells were designed into several groups: control group, PGE_2(0,4,40,400,4000,40000nM) group, EGCG (12.5,25,50,100μg/mL) group, PGE_2(4,40,400,4000)+EGCG(100μg/mL) group, ONO-DI-004(4,40,400,4000nM) group,ONO-DI-004+EGCG (100μg/mL) group, ONO-8711(210nM,1,5,10μM) group.MTT assay was performed to determine the proliferation of HepG2cells; Would healing assay and Transwell filter cell migration assay were used to determine themigration of HepG2cells; Western blot and Immunofluorescence microscopy wereused to determine the expression of EP1, Gq and Bcl-2protein in HepG2cells; Elisaassay was performed to determine the PGE_2production in serum from patients withHCC or in HepG2cells; Flow cytomertry was performed to determine the cell cycleand apoptosis of HepG2cells.
Results
1. Serum PGE_2level was higher in HCC patientsCompared with the serum PGE_2level from normal people, serum PGE_2level washigher in HCC patients.
2. That EGCG reduced PGE_2and VEGF levels, and lowered the expression ofEP1and Bcl-2is the important role of EGCG on HCC inhibitionCompared with control group, EGCG (12.5,25,50,100μg/mL) reduced PGE_2and VEGF levels in HepG2in dose-dependent way (r=0.758, r=0.958). EP_1expression was higher in the MHCC-97L and HepG2cells compared with humanhepatocytes L02cells. EGCG significantly inhibited EP1expression andONO-DI-004-induced Bcl-2expression in HCC cells.
3. EGCG significantly inhibited PGE_2and ONO-DI-004-induced proliferationand migration of HepG2cells.Elisa assay was used to detected the effects of EGCG (12.5,25,50,100μg/mL)on proliferation of HepG2.100μg/mL EGCG significantly inhibited HepG2growthafter24h incubation, the mean inhibition ratio was41%(r=0.8). EGCG significantlyinhibited HepG2growth. Wound healing assay and Transwell assay were used to testEGCG and ONO-8711suppressed migration of HepG2and EGCG inhibited PGE_2orONO-DI-004-induced migration of HepG2(**P<0.01).
3.3EGCG induced the apoptosis of HepG2cells.HepG2cells were incubated with ONO-DI-004(400nM)、PGE_2(4μM)、EGCG(100μg/mL)、 EGCG (100μg/mL)+ONO-DI-004(400nM) or EGCG (100μg/mL)+PGE_2(4μM) after24h. The apoptosis ratio in control group was(2.36±2.51)%, that was (16.8±1.73)%in EGCG (100μg/mL) group. EGCGsignificantly induced HepG2cell apoptosis (**P<0.01). The apoptosis ratio inONO-DI-004(400nM) was (0.6±1.86)%, that was (12.25±2.64)%in EGCG (100μg/mL)+ONO-DI-004(400nM) group.
Conclusion
1. High serum PGE_2levels in HCC patients indicated the important role of PGE_2inHCC patients;
2. EP1expression in HCC cell lines compared with normal liver cells was abnormalelevation of PGE_2, which indicated that PGE_2might promote HCC by binding to EP_1receptors.
3. EGCG inhibited PGE_2or ONO-DI-004-induced proliferation and migration ofHepG2, and induced cell cycle arrest and apoptosis. These finding suggested thatinducing cell apoptosis and inhibiting proliferation, migration and cell cycle were theimportant role of EGCG on anti-HCC.
4. EGCG reduced VEGF and PGE_2levels in HepG2cells, and inhibited EP_1expression and ONO-DI-004-induced Bcl-2expression but almost no effects on Gqprotein. That reducing PGE_2, VEGF and EP1and Bcl-2expression was one ofmechanisms of EGCG on proliferation and migration of HepG2cells.
目的：
观察HCC患者血清中PGE_2水平及EP_1在HCC细胞和人肝细胞中的表达，分析PGE_2及EP_1激动剂ONO-DI-004对HCC增殖和移行的相关性，研究EGCG对PGE_2或ONO-DI-004刺激的HCC的抑制作用及对HCC细胞周期、凋亡、PGE_2、EP_1和Bcl-2表达的影响，初步探讨EGCG抗HCC的作用靶点和机制。
方法：
HepG2细胞设置组别为：对照组、PGE_2(0,4,40,400,4000,40000nM)组、EGCG (12.5,25,50,100μg/mL)组、PGE_2(4,40,400,4000)+EGCG(100μg/mL)组、ONO-DI-004(4,40,400,4000nM)组、ONO-DI-004+EGCG(100μg/mL)组、ONO-8711(210nM,1,5,10μM)组。MTT法检测HepG2的增殖；细胞划痕实验和Transwell侵袭实验检测HepG2的移行；Western blot assay和免疫荧光实验检测HepG2中EP_1、Gq和Bcl-2蛋白的表达；酶联免疫分析法检测HCC患者血清PGE_2及HepG2产生PGE_2和VEGF的水平；流式细胞技术检测HepG2细胞周期和凋亡。
结果：
1. HCC患者的血清中PGE_2的水平呈高表达与正常志愿者血清中的PGE_2水平比较，HCC患者的血浆中PGE_2的水平呈高表达。
2.降低PGE_2和VEGF水平、下调EP_1和Bcl-2的表达是EGCG抑制HCC的重要作用与对照组相比，EGCG (12.5,25,50,100μg/mL)显著降低HepG2中PGE_2和VEGF水平。EP_1在肝癌细胞株MHCC-97L和HepG2中的表达明显高于在人肝细胞株L02中的表达。EGCG (100μg/ml)能显著抑制EP_1受体以及ONO-DI-004诱导的Bcl-2的表达(**P<0.01)。
3. EGCG对外源性PGE_2或ONO-DI-004刺激HCC增殖和移行具有显著的抑制作用
观察EGCG (12.5,25,50,100μg/mL)作用于HepG2后对细胞的增殖作用，100μg/mL EGCG对HepG2作用24h后可显著抑制HepG2的生长(**P<0.01),细胞的平均抑制率为41%。24h的药物浓度与抑制率具有相关性(r=0.8，P=0.02)。EGCG对HepG2具有显著抑制作用。细胞划痕实验和Transwell侵袭实验观察PGE_2(4μM)和ONO-DI-004(400nM)刺激后，HepG2移行较对照组明显增加，EGCG和ONO-8711均能显著抑制HepG2移行，且给予EGCG (100μg/mL)后可显著降低PGE_2和ONO-DI-004刺激的HepG2的移行(**P<0.01)。
4. EGCG能促进HepG2凋亡
流式细胞术检测细胞凋亡率，HepG2经ONO-DI-004(400nM)、PGE_2(4μM)、EGCG (100μg/mL)、EGCG (100μg/mL)+ONO-DI-004(400nM)以及EGCG (100μg/mL)+PGE_2(4μM)作用24h，对照组的细胞凋亡率为(2.36±2.51)%, EGCG (100μg/mL)处理组的凋亡率为(16.8±1.73)%，EGCG (100μg/mL)处理组与对照组的细胞凋亡率相比差异性显著(**P<0.01)。ONO-DI-004(400nM)处理组的凋亡率为(0.6±1.86)%, EGCG (100μg/mL)+ONO-DI-004(400nM)处理组的凋亡率为(12.25±2.64)%，两组间的差异具有显著性(**P<0.01)。EGCG (100μg/mL)可显著的诱导HepG2细胞的凋亡，对PGE_2、ONO-DI-004刺激的HepG2细胞也有明显的促凋亡作用。
结论
1. HCC患者血清中PGE_2表达异常升高，提示PGE_2在HCC患者中发挥重要作用；
2. HCC细胞株中EP1表达较正常肝细胞异常升高，PGE_2可能通过EP1发挥促HCC作用；
3. EGCG呈浓度依赖性抑制由PGE_2和ONO-DI-004刺激引起的HepG2的增殖和转移，抑制HCC异常增殖、移行、细胞周期，诱导凋亡是EGCG的重要作用；
4. EGCG抑制HepG2产生VEGF和PGE_2，降低EP1及ONO-DI-004刺激的Bcl-2的表达，但对Gq蛋白的表达没有影响，降低PGE_2和VEGF水平、下调EP1和Bcl-2的表达是EGCG抑制HCC增殖和移行、诱导凋亡的重要机制之一。
(Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory ofAnti-inflammatory and Immunopharmacology, Anhui Medical University, Ministryof Education, Anhui Key Laboratory of Research and Development of ChineseMedicine, Engineering Technology Research Center of Anti-inflammatory andImmunodrugs in Anhui Province, Scientific and Technological Team ofAnti-inflammatory and Immunopharmacology of Chinese Medicine in AnhuiProvince, the115industial innovation team of basic and applied research intoanti-inflammation and immunodrugs in anhui province, Hefei,230032)
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the thirdmost common cause of death from cancer worldwide. In China HCC accounts for55%of all cases worldwide, and is the second leading cause of cancer death. So farthe tumorigenic mechanism of HCC remains undefined. And the antineoplastic agentsoften achieve low antineoplastic activity at the expense of close to unacceptabletoxicity. Therefore， there is a tremendous interest and urgency to search forrecurrence/metastasis related biomarkers and new agents with high effectiveness andlow toxicity for inhibiting HCC invasion and metastasis, which would better providenovel measures for intervention. The study found that the well-differentiated HCCexpressed COX-2more frequently and strongly than less-differentiated HCC,indicating that COX-2may participate in the early onset of HCC process. The level ofCOX-2expression and Akt phosphorylation was correlated positively in culturedHCC cells and human liver cancer tissues. In vitro and in vivo experiments showedthat COX-2inhibited the activity of caspases3, and caspases9, reduced theexpression of p53and Bax, enhanced Akt activity. COX-2expression was closely
related to HCC occurrence and development. More and more evidences revealed thatCOX-2-derived prostaglandin E2(PGE_2) plays pivotal roles in tumor invasion. InHCC the level of PGE_2was highest compared with other PG productions. PGE_2exertsits biological actions primarily via their respective G protein-coupled receptors(GPCR) superfamily of prostaglandin E receptor (EP). Reports showed that EP_1expression was most abundant in HCC.(-)-epigallocatechin-3-gallate (EGCG) is apolyphenolic compound from tea and natural plants that has been shown to haveanti-tumor activities. However, the delicate mechanisms and signaling pathwaysunderlying the potential anticancer effects of EGCG in HCC cells remain unclear.
This study is designed to investigate the possible mechanism of PGE_2/EP_1signaling pathway in HCC and the effects of EGCG on this signaling. Thus, thesefindings might provide the novel target for HCC treatment and the rationale forEGCG served as a novel therapeutic agent to treat HCC patients, and future study onits clinical application might be worthwhile.
AIMS:
To observe EP1expression in HCC cells and human hepatocyte L02and theserum PGE_2levels of patients with HCC, to analysis of the effects of PGE_2and theEP1agonist ONO-DI-004on proliferation and migration of HCC, to investigate theeffects of EGCG on cell cycle, apoptosis, PGE_2, EP1and Bcl-2expression of HCC, todiscuss the anti-HCC mechanism of EGCG.
METHODS:
HepG2cells were designed into several groups: control group, PGE_2(0,4,40,400,4000,40000nM) group, EGCG (12.5,25,50,100μg/mL) group, PGE_2(4,40,400,4000)+EGCG(100μg/mL) group, ONO-DI-004(4,40,400,4000nM) group,ONO-DI-004+EGCG (100μg/mL) group, ONO-8711(210nM,1,5,10μM) group.MTT assay was performed to determine the proliferation of HepG2cells; Would healing assay and Transwell filter cell migration assay were used to determine themigration of HepG2cells; Western blot and Immunofluorescence microscopy wereused to determine the expression of EP1, Gq and Bcl-2protein in HepG2cells; Elisaassay was performed to determine the PGE_2production in serum from patients withHCC or in HepG2cells; Flow cytomertry was performed to determine the cell cycleand apoptosis of HepG2cells.
Results
1. Serum PGE_2level was higher in HCC patientsCompared with the serum PGE_2level from normal people, serum PGE_2level washigher in HCC patients.
2. That EGCG reduced PGE_2and VEGF levels, and lowered the expression ofEP1and Bcl-2is the important role of EGCG on HCC inhibitionCompared with control group, EGCG (12.5,25,50,100μg/mL) reduced PGE_2and VEGF levels in HepG2in dose-dependent way (r=0.758, r=0.958). EP_1expression was higher in the MHCC-97L and HepG2cells compared with humanhepatocytes L02cells. EGCG significantly inhibited EP1expression andONO-DI-004-induced Bcl-2expression in HCC cells.
3. EGCG significantly inhibited PGE_2and ONO-DI-004-induced proliferationand migration of HepG2cells.Elisa assay was used to detected the effects of EGCG (12.5,25,50,100μg/mL)on proliferation of HepG2.100μg/mL EGCG significantly inhibited HepG2growthafter24h incubation, the mean inhibition ratio was41%(r=0.8). EGCG significantlyinhibited HepG2growth. Wound healing assay and Transwell assay were used to testEGCG and ONO-8711suppressed migration of HepG2and EGCG inhibited PGE_2orONO-DI-004-induced migration of HepG2(**P<0.01).
3.3EGCG induced the apoptosis of HepG2cells.HepG2cells were incubated with ONO-DI-004(400nM)、PGE_2(4μM)、EGCG(100μg/mL)、 EGCG (100μg/mL)+ONO-DI-004(400nM) or EGCG (100μg/mL)+PGE_2(4μM) after24h. The apoptosis ratio in control group was(2.36±2.51)%, that was (16.8±1.73)%in EGCG (100μg/mL) group. EGCGsignificantly induced HepG2cell apoptosis (**P<0.01). The apoptosis ratio inONO-DI-004(400nM) was (0.6±1.86)%, that was (12.25±2.64)%in EGCG (100μg/mL)+ONO-DI-004(400nM) group.
Conclusion
1. High serum PGE_2levels in HCC patients indicated the important role of PGE_2inHCC patients;
2. EP1expression in HCC cell lines compared with normal liver cells was abnormalelevation of PGE_2, which indicated that PGE_2might promote HCC by binding to EP_1receptors.
3. EGCG inhibited PGE_2or ONO-DI-004-induced proliferation and migration ofHepG2, and induced cell cycle arrest and apoptosis. These finding suggested thatinducing cell apoptosis and inhibiting proliferation, migration and cell cycle were theimportant role of EGCG on anti-HCC.
4. EGCG reduced VEGF and PGE_2levels in HepG2cells, and inhibited EP_1expression and ONO-DI-004-induced Bcl-2expression but almost no effects on Gqprotein. That reducing PGE_2, VEGF and EP1and Bcl-2expression was one ofmechanisms of EGCG on proliferation and migration of HepG2cells.
引文
1Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA,Schroeder I, Factor VM, Thorgeirsson SS.. Mechanistic and prognosticsignificance of aberrant methylation in the molecular pathogenesis of humanhepatocellular carcinoma. J Clin Invest2007;117(9):2713–22.
2Breinig M, Rieker R, Eiteneuer E, Wertenbruch T, Haugg AM, Helmke BM,Schirmacher P, Kern MA. Differential expression of E-prostanoid receptors inhuman hepatocellular carcinoma. Int J Cancer2008;122(3):547-57.
3Leng J, Han C, Demetris AJ, Michalopoulos GK, Wu T. Cyclooxygenase-2promotes hepatocellular carcinoma cell growth through Akt activation:evidence for Akt inhibition in celecoxib-induced apoptosis. Hepatology2003;38(3):756–68.
4周士珍,吴强,吴正升,凌晓光,杨枫.乳腺癌中环氧化酶-2的表达及其与VEGF、MVD、MMP-9、 TIMP-1的关系.临床与实验病理学杂志2005;20(4):442-5.
5Tang TC, Poon RT, Lau CP, Xie D, Fan ST. Tumor cyclooxygenase-2levelscorrelate with tumor invasiveness in human hepatocellular carcinoma. World JGastroenterol2005;11(13):1896-902.
6Kern MA, Schubert D, Sahi D, Sch neweiss MM, Moll I, Haugg AM, DienesHP, Breuhahn K, Schirmacher P. Proapoptotic and antiproliferative potentialof selective cyclooxygenase-2inhibitors in human liver tumor cells.Hepatology2002;36(4Pt1):885-94.
7Kern MA, Sch neweiss MM, Sahi D, Bahlo M, Haugg AM, Kasper HU,Dienes HP, K ferstein H, Breuhahn K, Schirmacher P. Cyclooxygenase-2inhibitors suppress the growth of human hepatocellular carcinoma implants innude mice. Carcinogenesis2004;25(7):1193-9.
8Kern MA, Haugg AM, Koch AF, Schilling T, Breuhahn K, Walczak H,Fleischer B, Trautwein C, Michalski C, Schulze-Bergkamen H, Friess H,Stremmel W, Krammer PH, Schirmacher P, Müller M. Cyclooxygenase-2inhibition induces apoptosis signaling via death receptors and mitochondria inhepatocellular carcinoma. Cancer Res2006;66(14):7059-66.
9Bae SH, Jung ES, Park YM, Kim BS, Kim BK, Kim DG, Ryu WS. Expressionof cyclooxygenase-2(COX-2) in hepatocellular carcinoma and growthinhibition of hepatoma cell lines by a COX-2inhibitor, NS-398. Clin CancerRes2001;7(5):1410-18.
10Sung YK, Hwang SY, Kim JO, Bae HI, Kim JC, Kim MK. The correlationbetween cyclooxygenase-2expression and hepatocellular carcinogenesis. MolCells2004;17(1):35-8.
11Sanghi S, MacLaughlin EJ, Jewell CW, Chaffer S, Naus PJ, Watson LE,Dostal DE. Cyclooxygenase-2inhibitors: a painful lesson. CardiovascHematol Disord Drug Targets2006;6(2):85-100.
12Zigrino P, L ffek S, Mauch C. Tumor-stroma interactions：their role in thecontrol of tumor cell invasion. Biochimie2005;87(3-4):321-28.
13Nakanishi M, Gokhale V, Meuillet EJ, Rosenberg DW. mPGES-1as a targetfor cancer suppression A comprehensive invited review "Phospholipase A(2)and lipid mediators". Biochimie2010;92(6):660-4.
14Williams CS, Mann M, DuBois RN. The role of cyclooxygenases ininflammation, cancer, and development. Oncogene1999;18(55):7908-16.
15张成平.前列腺素E的生物学效应及在肝脏病理生理作用.国外医学消化系统疾病分册1995;15(2):88-91.
16Han C, Demetris AJ, Michalopoulos G, Shelhamer JH, Wu T.85-kDa cPLA(2)plays a critical role in P cription in human hepatoma cells. Am J PhysiolGastrointest Liver Physiol2002;282(4): G586-97.
17Hagi A, Nakayama M, Miura Y, Yagasaki K. Effects of a fish oil-basedemulsion on rat hepatoma cell invasion in culture. Nutrition2007;23(11-12):871-7.
18Mayoral R, Fernández-Martínez A, Boscá L, Martín-Sanz P. Prostaglandin E2promotes migration and adhesion in hepatocellular carcinoma cells.Carcinogenesis2005;26(4):753-61.
19Miyaura C, Inada M,, Suzawa T, Sugimoto Y, Ushikubi F, Ichikawa A,Narumiya S, Suda T. Impaired bone resorption to prostaglandin E2inprostaglandin E receptor EP4-knockout mice. J Biol Chem2000;275(26):19819-23.
20Chell S, Kaidi A,, Williams AC, Paraskeva C. Mediators of PGE2synthesisand signalling downstream of COX-2represent potential targets for theprevention/treatment of colorectal cancer. Biochim Biophys Acta2006;1766(1):104-19.
21Han C, Michalopoulos GK, Wu T. Prostaglandin E2receptor EP1transactivates EGFR/MET receptor tyrosine kinases and enhancesinvasiveness in human hepatocellular carcinoma cells. J Cell Physiol2006;207(1):261-70.
22Liu JF, Fong YC, Chang CS, Huang CY, Chen HT, Yang WH, Hsu CJ, JengLB, Chen CY, Tang CH. Cyclooxygenase-2enhances alpha2beta1integrinexpression and cell migration via EP1dependent signaling pathway in humanchondrosarcoma cell. Mol Cancer2010;9:43.
23Kawamori T, Uchiya N, Nakatsugi S, Watanabe K, Ohuchida S, Yamamoto H,Maruyama T, Kondo K, Sugimura T, Wakabayashi K. Chemopreventiveeffects of ONO-8711, a selective prostaglandin E receptor EP(1) antagonist,on breast cancer development. Carcinogenesis2001;22(12):2001-4.
24Kawamori T, Kitamura T, Watanabe K, Uchiya N, Maruyama T, Narumiya S,Sugimura T, Wakabayashi K. Prostaglandin E receptor subtype EP1deficiency inhibits colon cancer development. Carcinogenesis2005;26(2):353-7.
25Hibasami H, Komiya T, Achiwa Y, Ohnishi K, Kojima T, Nakanishi K,Akashi K, Hara Y. Induction of apoptosis in human stomach cancer cells bygreen tea catechins. Oncol Rep1998;5(2):527-29.
26Nakachi K, Matsuyama S, Miyake S, Suganuma M, Imai K. Preventive effectsof drinking green tea on cancer and cardiovascular disease: epidemiologicalevidence for multiple targeting prevention. Biofactors2000;13(1-4):49-54.
27Sartippour MR, Heber D, Ma J, Lu Q, Go VL, Nguyen M. Green tea and itscatechins inhibit breast cancer xenografts. Nutr Cancer2001;40(2):149-56.
28Shimizu M, Weinstein IB. Modulation of signal transduction by tea catechinsand related phytochemicals. Mutat Res2005;591(1-2):147-60.
29Khan N, Afaq F, Saleem M, Ahmad N, Mukhtar H. Targeting multiplesignaling pathways by green tea polyphenol (-)-epigallocatechin-3-gallate.Cancer Res2006;66(5):2500-5.
30Yang CS, Wang X, Lu G, Picinich SC. Cancer prevention by tea: animalstudies, molecular mechanisms and human relevance. Nat Rev Cancer2009;9(6):429-39.
31Devika PT, Stanely Mainzen Prince P.(-)Epigallocatechin-gallate (EGCG)prevents mitochondrial damage in isoproterenol-induced cardiac toxicity inalbino Wistar rats: a transmission electron microscopic and in vitro study.Pharmacol Res2008;57(5):351-7.
32Ermakova SP, Kang BS, Choi BY, Choi HS, Schuster TF, Ma WY, Bode AM,Dong Z.(-)-Epigallocatechin gallate overcomes resistance toetoposide-induced cell death by targeting the molecular chaperoneglucose-regulated protein78. Cancer Res2006;66(18):9260-9.
33Maiti TK, Ghosh KS, Dasgupta S. Interaction of (-)-epigallocatechin-3-gallatewith human serum albumin: fluorescence, fourier transform infrared, circulardichroism, and docking studies. Proteins2006;64(2):355-62.
34Patra SK. Dissecting lipid raft facilitated cell signaling pathways in cancer.Biochim Biophys Acta2008;1785(2):182-206.
35Patra SK, Rizzi F, Silva A, Rugina DO, Bettuzzi S. Molecular targets of(-)-epigallocatechin-3-gallate (EGCG): specificity and interaction withmembrane lipid rafts. J Physiol Pharmacol2008;59(Suppl9):217-35.
36Leone M, Zhai D, Sareth S, Kitada S, Reed JC, Pellecchia M. Cancerprevention by tea polyphenols is linked to their direct inhibition ofantiapoptotic Bcl-2-family proteins. Cancer Res2003;63(23):8118-21.
37Sánchez-Huerta V, Gutiérrez-Sánchez L, Flores-Estrada J.(-)-Epigallocatechin3-gallate (EGCG) at the ocular surface inhibits cornealneovascularization. Med Hypotheses2011;76(3):311-3.
38Ye F, Zhang GH, Guan BX, Xu XC. Suppression of esophageal cancer cellgrowth using curcumin,(-)-epigallocatechin-3-gallate and lovastatin. World JGastroenterol2012;18(2):126-35.
39Jung YD, Ellis LM. Inhibition of tumour invasion and angiogenesis byepigallocatechin gallate (EGCG), a major component of green tea. Int J ExpPathol2001;82(6):309-16.
40Nishikawa T, Nakajima T, Moriguchi M, Jo M, Sekoguchi S, Ishii M,Takashima H, Katagishi T, Kimura H, Minami M, Itoh Y, Kagawa K,Okanoue T. A green tea polyphenol, epigalocatechin-3-gallate, inducesapoptosis of human hepatocellular carcinoma, possibly through inhibition ofBcl-2family proteins. J Hepatol2006;44(6):1074-82.
41Wu T. Cyclooxygenase-2in hepatocellular carcinoma. Cancer Treat Rev.2006;32(1):28-44.
42Cheng AS, Chan HL, To KF, Leung WK, Chan KK, Liew CT, Sung JJ.Cyclooxygenase-2pathway correlates with vascular endothelial growth factorexpression and tumor angiogenesis in hepatitis B virus-associatedhepatocellular carcinoma. Int J Oncol2004;24(4):853-60.
43Koga H, Sakisaka S, Ohishi M, Kawaguchi T, Taniguchi E, Sasatomi K,Harada M, Kusaba T, Tanaka M, Kimura R, Nakashima Y, Nakashima O,Kojiro M, Kurohiji T, Sata M. Expression of cyclooxygenase-2in humanhepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology1999;29(3):688-96.
44Fernández-Martínez A, Mollá B, Mayoral R, Boscá L, Casado M, Martín-SanzP. Cyclo-oxygenase2expression impairs serum-withdrawal-induced apoptosisin liver cells. Biochem J2006;398(3):371-80.
45Li T, Yang Y,, Hua X, Wang G, Liu W, Jia C, Tai Y, Zhang Q, Chen G.Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunctionvia PGE2and IDO. Cancer Lett2012;318(2):154-61.
46Mayoral R, Fernández-Martínez A, Boscá L, Martín-Sanz P. Prostaglandin E2promotes migration and adhesion in hepatocellular carcinoma cells.Carcinogenesis2005;26(4):753-61.
47徐晓丽;李刘.喉癌手术前后血浆前列腺素E-2水平变化及临床意义.临床耳鼻咽喉科杂志2000;14(3):106-07.
48Cordes T, Hoellen F, Dittmer C, Salehin D, Kümmel S, Friedrich M, K ster F,Becker S, Diedrich K, Thill M. Correlation of prostaglandin metabolizingenzymes and serum PGE2levels with vitamin D receptor and serum25(OH)2D3levels in breast and ovarian cancer. Anticancer Res2012;32(1):351-7.
49Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP.Long-term effect of aspirin on colorectal cancer incidence and mortality:20-year follow-up of five randomised trials. Lancet Infect Dis2010;376(9754):1741–50.
50Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW.Effect of daily aspirin on long-term risk of death due to cancer: analysis ofindividual patient data from randomised trials. Lancet2011;377(9759):31-41.
51金娟，何义富，魏伟.肝细胞癌PGE2受体的信号转导通路及其可能药物作用靶点.中国新药杂志2008;17(7):1470-73.
52Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med2004;351(17):1709-11.
53Jones SC. Relative thromboembolic risks associated with COX-2inhibitors.Ann Pharmacother2005;39(7-8):1249-59.
54Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K,Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA;Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators.Cardiovascular events associated with rofecoxib in a colorectal adenomachemoprevention trial. N Engl J Med2005;352(11):1092-102.
55Chen XL, Wang Q, Cao LQ, Huang XH, Fu XH, Tan HX, Zhen MC, Chen JS.Epigallocatechin-3-gallate induces apoptosis in human hepatocellularcarcinoma cells. Zhonghua Yi Xue Za Zhi2008;88(36):2524-8.
56Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenicswitch during tumorigenesis. cell1996;86(3):353-64.
1Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA,Schroeder I, Factor VM, Thorgeirsson SS.. Mechanistic and prognosticsignificance of aberrant methylation in the molecular pathogenesis of humanhepatocellular carcinoma. J Clin Invest2007;117(9):2713–22.
2Breinig M, Rieker R, Eiteneuer E, Wertenbruch T, Haugg AM, Helmke BM,Schirmacher P, Kern MA. Differential expression of E-prostanoid receptors inhuman hepatocellular carcinoma. Int J Cancer2008;122(3):547-57.
3Mohammed NA, Abd El-Aleem SA,, El-Hafiz HA, McMahon RF.Distribution of constitutive (cox-1) and inducible (cox-2) cyclooxygenase inpostviral human liver cirrhosis: a possible role for cox-2in the pathogenesis ofliver cirrhosis. J Clin Pathol2004(4);57:350-54.
4Gridley G, McLaughlin JK, Ekbom A, Klareskog L, Adami HO, Hacker DG,Hoover R, Fraumeni JF Jr. Incidence of cancer among patients withrheumatoid arthritis. J Natl Cancer Inst1993;85(4):307-11.
5Koga H, Sakisaka S, Ohishi M, Kawaguchi T, Taniguchi E, Sasatomi K,Harada M, Kusaba T, Tanaka M, Kimura R, Nakashima Y, Nakashima O,Kojiro M, Kurohiji T, Sata M. Expression of cyclooxygenase-2in humanhepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology1999;29(3):688–96.
6Fernández-Martínez A, Mollá B, Mayoral R, Boscá L, Casado M, Martín-SanzP. Cyclo-oxygenase2expression impairs serum-withdrawal-induced apoptosisin liver cells. Biochem J2006;398(3):371-80.
7Leng J, Han C, Demetris AJ, Michalopoulos GK, Wu T. Cyclooxygenase-2promotes hepatocellular carcinoma cell growth through Akt activation:evidence for Akt inhibition in celecoxib-induced apoptosis. Hepatology2003;38(3):756–68.
8Rahman MA, Dhar DK, Yamaguchi E, Maruyama S, Sato T, Hayashi H, OnoT, Yamanoi A, Kohno H, Nagasue N. Coexpression of inducible nitric oxidesynthase and COX-2in hepatocellular carcinoma and surrounding liver:possible involvement of COX-2in the angiogenesis of hepatitis Cvirus-positive cases. Clin Cancer Res2001;7(5):1325-32.
9Kern MA, Haugg AM, Koch AF, Schilling T, Breuhahn K, Walczak H,Fleischer B, Trautwein C, Michalski C, Schulze-Bergkamen H, Friess H,Stremmel W, Krammer PH, Schirmacher P, Müller M. Cyclooxygenase-2inhibition induces apoptosis signaling via death receptors and mitochondria inhepatocellular carcinoma. Cancer Res2006;66(14):7059-66.
10Kern MA, Sch neweiss MM, Sahi D, Bahlo M, Haugg AM, Kasper HU,Dienes HP, K ferstein H, Breuhahn K, Schirmacher P. Cyclooxygenase-2inhibitors suppress the growth of human hepatocellular carcinoma implants innude mice. Carcinogenesis2004;25(7):1193-9.
11Kern MA, Schubert D, Sahi D, Sch neweiss MM, Moll I, Haugg AM, DienesHP, Breuhahn K, Schirmacher P. Proapoptotic and antiproliferative potentialof selective cyclooxygenase-2inhibitors in human liver tumor cells.Hepatology2002;36(4Pt1):885-94.
12Bae SH, Jung ES, Park YM, Kim BS, Kim BK, Kim DG, Ryu WS. Expressionof cyclooxygenase-2(COX-2) in hepatocellular carcinoma and growthinhibition of hepatoma cell lines by a COX-2inhibitor, NS-398. Clin CancerRes2001;7(5):1410-18.
13Sung YK, Hwang SY, Kim JO, Bae HI, Kim JC, Kim MK. The correlationbetween cyclooxygenase-2expression and hepatocellular carcinogenesis. MolCells2004;17(1):35-8.
14Sanghi S, MacLaughlin EJ, Jewell CW, Chaffer S, Naus PJ, Watson LE,Dostal DE. Cyclooxygenase-2inhibitors: a painful lesson. CardiovascHematol Disord Drug Targets2006;6(2):85-100.
15Togo S, Chen H, Takahashi T, Kubota T, Matsuo K, Morioka D, Watanabe K,Yamamoto H, Nagashima Y, Shimada H. Prostaglandin E (1) ImprovesSurvival Rate After95%Hepatectomy in Rats. J Surg Res2007;146(1):66-72.
16张成平.前列腺素E的生物学效应及在肝脏病理生理作用.国外医学消化系统疾病分册1995;15(2):88-91.
17缪新权，鲁慎文，黄宜雄，李桂云，朱丽明. PGE1治疗慢性乙型肝炎51例.新消化病学杂志1995;3(2):107-08.
18Han C, Demetris AJ, Michalopoulos G, Shelhamer JH, Wu T.85-kDa cPLA(2)plays a critical role in P cription in human hepatoma cells. Am J PhysiolGastrointest Liver Physiol2002;282(4): G586-97.
19Williams CS, Mann M, DuBois RN. The role of cyclooxygenases ininflammation, cancer, and development. Oncogene1999;18(55):7908-16.
20Hagi A, Nakayama M, Miura Y, Yagasaki K. Effects of a fish oil-basedemulsion on rat hepatoma cell invasion in culture. Nutrition2007;23(11-12):871-7.
21朱东，叶蕾，朱肖鸿，严颖.前列腺素E1治疗高黄疸慢性乙型肝炎36例.浙江中西医结合杂志2005;15(7):439-40.
22徐启恒，曹红，周四海.前列腺素E1治疗慢性病毒性肝炎、肝硬化及重症肝炎的疗效.中国临床药学杂志1999;8(4):211-13.
23Chun KS, Akunda JK, Langenbach R. Cyclooxygenase-2inhibitsUVB-induced apoptosis in mouse skin by activating the prostaglandin E2receptors, EP2and EP4. Cancer Res2007;67(5):2015–21.
24Chu AJ, Chou TH, Chen BD. Prevention of colorectal cancer using COX-2inhibitors: basic science and clinical applications. Front Biosci2004;9:2697–713.
25Wu T, Leng J, Han C, Demetris AJ. The cyclooxygenase-2inhibitor celecoxibblocks phosphorylation of Akt and induces apoptosis in humancholangiocarcinoma cells. Mol Cancer Ther2004;3(3):299–307.
26Mutoh M, Takahashi M, Wakabayashi K. Roles of prostanoids in coloncarcinogenesis and their potential targeting for cancer chemoprevention. CurrPharm Des2006;12(19):2375–82.
27Wang D, Dubois RN. Cyclooxygenase-2: a potential target in breast cancer.Semin Oncol2004;31(1Suppl3):64–73.
28Greenhough A, Wallam CA，Greenhough A WC, Hicks DJ, Moorghen M,Williams AC, Paraskeva C. The proapoptotic BH3-only protein Bim isdownregulated in a subset of colorectal cancers and is repressed byantiapoptotic COX-2/PGE(2) signalling in colorectal adenoma cells.Oncogene2010;29(23):3398–410.
29Basu GD, Pathangey LB, Tinder TL, Lagioia M, Gendler SJ, Mukherjee P..Cyclooxygenase-2inhibitor induces apoptosis in breast cancer cells in an invivo model of spontaneous metastatic breast cancer. Mol Cancer Res2004;2(11):632–42.
30Strong VE, Winter J, Yan Z, Smyth GP, Mestre JR, Maddali S, Schaefer PA,Yurt RW, Stapleton PP, Daly JM. Prostaglandin E2receptors EP2and EP4aredown-regulated in human mononuclear cells after injury. Surgery2001;130(2):249-55.
31Han C, Michalopoulos GK, Wu T. Prostaglandin E2receptor EP1transactivates EGFR/MET receptor tyrosine kinases and enhancesinvasiveness in human hepatocellular carcinoma cells. J Cell Physiol2006;207(1):261-70.
32Kawamori T, Uchiya N, Nakatsugi S, Watanabe K, Ohuchida S, Yamamoto H,Maruyama T, Kondo K, Sugimura T, Wakabayashi K. Chemopreventiveeffects of ONO-8711, a selective prostaglandin E receptor EP(1) antagonist,on breast cancer development. Carcinogenesis2001;22(12):2001-4.
33Niho N, Mutoh M, Kitamura T, Takahashi M, Sato H, Yamamoto H,Maruyama T, Ohuchida S, Sugimura T, Wakabayashi K. Suppression ofazoxymethane-induced colon cancer development in rats by a prostaglandin Ereceptor EP1-selective antagonist. Cancer Sci2005;96(5):260-64.
34Bilson HA, Mitchell DL, Ashby B. Human prostaglandin EP3receptorisoforms show different agonist-induced internalization patterns. FEBS Lett2004;572(1-3):271-75.
35Yamaki T, Endoh K, Miyahara M, Nagamine I, Thi Thu Huong N, Sakurai H,Pokorny J, Yano T. Prostaglandin E2activates Src signaling in lungadenocarcinoma cell via EP3. Cancer Lett2004;214(1):115-20.
36Yano T, Zissel G, Muller-Qernheim J, Jae Shin S, Satoh H, Ichikawa T.Prostaglandin E2reinforces the activation of Ras signal pathway in lungadenocarcinoma cells via EP3. FEBS Lett2002;518(1-3):154-58.
37Shoji Y, Takahashi M, Kitamura T, Watanabe K, Kawamori T, Maruyama T,Sugimoto Y, Negishi M, Narumiya S, Sugimura T, Wakabayashi K.Downregulation of prostaglandin E receptor subtype EP3during colon cancerdevelopment. Gut2004;53(8):1151-58.
38Gómez-Hernández A, Martín-Ventura JL, Sánchez-Galán E, Vidal C, OrtegoM, Blanco-Colio LM, Ortega L, Tu ón J, Egido J. Overexpression of COX-2,Prostaglandin E synthase-1and prostaglandin E receptors in bloodmononuclear cells and plaque of patients with carotid atherosclerosis:regulation by nuclear factor-kappaB. Atherosclerosis2006;187(1):139-49.
2Breinig M, Rieker R, Eiteneuer E, Wertenbruch T, Haugg AM, Helmke BM,Schirmacher P, Kern MA. Differential expression of E-prostanoid receptors inhuman hepatocellular carcinoma. Int J Cancer2008;122(3):547-57.
3Leng J, Han C, Demetris AJ, Michalopoulos GK, Wu T. Cyclooxygenase-2promotes hepatocellular carcinoma cell growth through Akt activation:evidence for Akt inhibition in celecoxib-induced apoptosis. Hepatology2003;38(3):756–68.
4周士珍,吴强,吴正升,凌晓光,杨枫.乳腺癌中环氧化酶-2的表达及其与VEGF、MVD、MMP-9、 TIMP-1的关系.临床与实验病理学杂志2005;20(4):442-5.
5Tang TC, Poon RT, Lau CP, Xie D, Fan ST. Tumor cyclooxygenase-2levelscorrelate with tumor invasiveness in human hepatocellular carcinoma. World JGastroenterol2005;11(13):1896-902.
6Kern MA, Schubert D, Sahi D, Sch neweiss MM, Moll I, Haugg AM, DienesHP, Breuhahn K, Schirmacher P. Proapoptotic and antiproliferative potentialof selective cyclooxygenase-2inhibitors in human liver tumor cells.Hepatology2002;36(4Pt1):885-94.
7Kern MA, Sch neweiss MM, Sahi D, Bahlo M, Haugg AM, Kasper HU,Dienes HP, K ferstein H, Breuhahn K, Schirmacher P. Cyclooxygenase-2inhibitors suppress the growth of human hepatocellular carcinoma implants innude mice. Carcinogenesis2004;25(7):1193-9.
8Kern MA, Haugg AM, Koch AF, Schilling T, Breuhahn K, Walczak H,Fleischer B, Trautwein C, Michalski C, Schulze-Bergkamen H, Friess H,Stremmel W, Krammer PH, Schirmacher P, Müller M. Cyclooxygenase-2inhibition induces apoptosis signaling via death receptors and mitochondria inhepatocellular carcinoma. Cancer Res2006;66(14):7059-66.
9Bae SH, Jung ES, Park YM, Kim BS, Kim BK, Kim DG, Ryu WS. Expressionof cyclooxygenase-2(COX-2) in hepatocellular carcinoma and growthinhibition of hepatoma cell lines by a COX-2inhibitor, NS-398. Clin CancerRes2001;7(5):1410-18.
10Sung YK, Hwang SY, Kim JO, Bae HI, Kim JC, Kim MK. The correlationbetween cyclooxygenase-2expression and hepatocellular carcinogenesis. MolCells2004;17(1):35-8.
11Sanghi S, MacLaughlin EJ, Jewell CW, Chaffer S, Naus PJ, Watson LE,Dostal DE. Cyclooxygenase-2inhibitors: a painful lesson. CardiovascHematol Disord Drug Targets2006;6(2):85-100.
12Zigrino P, L ffek S, Mauch C. Tumor-stroma interactions：their role in thecontrol of tumor cell invasion. Biochimie2005;87(3-4):321-28.
13Nakanishi M, Gokhale V, Meuillet EJ, Rosenberg DW. mPGES-1as a targetfor cancer suppression A comprehensive invited review "Phospholipase A(2)and lipid mediators". Biochimie2010;92(6):660-4.
14Williams CS, Mann M, DuBois RN. The role of cyclooxygenases ininflammation, cancer, and development. Oncogene1999;18(55):7908-16.
15张成平.前列腺素E的生物学效应及在肝脏病理生理作用.国外医学消化系统疾病分册1995;15(2):88-91.
16Han C, Demetris AJ, Michalopoulos G, Shelhamer JH, Wu T.85-kDa cPLA(2)plays a critical role in P cription in human hepatoma cells. Am J PhysiolGastrointest Liver Physiol2002;282(4): G586-97.
17Hagi A, Nakayama M, Miura Y, Yagasaki K. Effects of a fish oil-basedemulsion on rat hepatoma cell invasion in culture. Nutrition2007;23(11-12):871-7.
18Mayoral R, Fernández-Martínez A, Boscá L, Martín-Sanz P. Prostaglandin E2promotes migration and adhesion in hepatocellular carcinoma cells.Carcinogenesis2005;26(4):753-61.
19Miyaura C, Inada M,, Suzawa T, Sugimoto Y, Ushikubi F, Ichikawa A,Narumiya S, Suda T. Impaired bone resorption to prostaglandin E2inprostaglandin E receptor EP4-knockout mice. J Biol Chem2000;275(26):19819-23.
20Chell S, Kaidi A,, Williams AC, Paraskeva C. Mediators of PGE2synthesisand signalling downstream of COX-2represent potential targets for theprevention/treatment of colorectal cancer. Biochim Biophys Acta2006;1766(1):104-19.
21Han C, Michalopoulos GK, Wu T. Prostaglandin E2receptor EP1transactivates EGFR/MET receptor tyrosine kinases and enhancesinvasiveness in human hepatocellular carcinoma cells. J Cell Physiol2006;207(1):261-70.
22Liu JF, Fong YC, Chang CS, Huang CY, Chen HT, Yang WH, Hsu CJ, JengLB, Chen CY, Tang CH. Cyclooxygenase-2enhances alpha2beta1integrinexpression and cell migration via EP1dependent signaling pathway in humanchondrosarcoma cell. Mol Cancer2010;9:43.
23Kawamori T, Uchiya N, Nakatsugi S, Watanabe K, Ohuchida S, Yamamoto H,Maruyama T, Kondo K, Sugimura T, Wakabayashi K. Chemopreventiveeffects of ONO-8711, a selective prostaglandin E receptor EP(1) antagonist,on breast cancer development. Carcinogenesis2001;22(12):2001-4.
24Kawamori T, Kitamura T, Watanabe K, Uchiya N, Maruyama T, Narumiya S,Sugimura T, Wakabayashi K. Prostaglandin E receptor subtype EP1deficiency inhibits colon cancer development. Carcinogenesis2005;26(2):353-7.
25Hibasami H, Komiya T, Achiwa Y, Ohnishi K, Kojima T, Nakanishi K,Akashi K, Hara Y. Induction of apoptosis in human stomach cancer cells bygreen tea catechins. Oncol Rep1998;5(2):527-29.
26Nakachi K, Matsuyama S, Miyake S, Suganuma M, Imai K. Preventive effectsof drinking green tea on cancer and cardiovascular disease: epidemiologicalevidence for multiple targeting prevention. Biofactors2000;13(1-4):49-54.
27Sartippour MR, Heber D, Ma J, Lu Q, Go VL, Nguyen M. Green tea and itscatechins inhibit breast cancer xenografts. Nutr Cancer2001;40(2):149-56.
28Shimizu M, Weinstein IB. Modulation of signal transduction by tea catechinsand related phytochemicals. Mutat Res2005;591(1-2):147-60.
29Khan N, Afaq F, Saleem M, Ahmad N, Mukhtar H. Targeting multiplesignaling pathways by green tea polyphenol (-)-epigallocatechin-3-gallate.Cancer Res2006;66(5):2500-5.
30Yang CS, Wang X, Lu G, Picinich SC. Cancer prevention by tea: animalstudies, molecular mechanisms and human relevance. Nat Rev Cancer2009;9(6):429-39.
31Devika PT, Stanely Mainzen Prince P.(-)Epigallocatechin-gallate (EGCG)prevents mitochondrial damage in isoproterenol-induced cardiac toxicity inalbino Wistar rats: a transmission electron microscopic and in vitro study.Pharmacol Res2008;57(5):351-7.
32Ermakova SP, Kang BS, Choi BY, Choi HS, Schuster TF, Ma WY, Bode AM,Dong Z.(-)-Epigallocatechin gallate overcomes resistance toetoposide-induced cell death by targeting the molecular chaperoneglucose-regulated protein78. Cancer Res2006;66(18):9260-9.
33Maiti TK, Ghosh KS, Dasgupta S. Interaction of (-)-epigallocatechin-3-gallatewith human serum albumin: fluorescence, fourier transform infrared, circulardichroism, and docking studies. Proteins2006;64(2):355-62.
34Patra SK. Dissecting lipid raft facilitated cell signaling pathways in cancer.Biochim Biophys Acta2008;1785(2):182-206.
35Patra SK, Rizzi F, Silva A, Rugina DO, Bettuzzi S. Molecular targets of(-)-epigallocatechin-3-gallate (EGCG): specificity and interaction withmembrane lipid rafts. J Physiol Pharmacol2008;59(Suppl9):217-35.
36Leone M, Zhai D, Sareth S, Kitada S, Reed JC, Pellecchia M. Cancerprevention by tea polyphenols is linked to their direct inhibition ofantiapoptotic Bcl-2-family proteins. Cancer Res2003;63(23):8118-21.
37Sánchez-Huerta V, Gutiérrez-Sánchez L, Flores-Estrada J.(-)-Epigallocatechin3-gallate (EGCG) at the ocular surface inhibits cornealneovascularization. Med Hypotheses2011;76(3):311-3.
38Ye F, Zhang GH, Guan BX, Xu XC. Suppression of esophageal cancer cellgrowth using curcumin,(-)-epigallocatechin-3-gallate and lovastatin. World JGastroenterol2012;18(2):126-35.
39Jung YD, Ellis LM. Inhibition of tumour invasion and angiogenesis byepigallocatechin gallate (EGCG), a major component of green tea. Int J ExpPathol2001;82(6):309-16.
40Nishikawa T, Nakajima T, Moriguchi M, Jo M, Sekoguchi S, Ishii M,Takashima H, Katagishi T, Kimura H, Minami M, Itoh Y, Kagawa K,Okanoue T. A green tea polyphenol, epigalocatechin-3-gallate, inducesapoptosis of human hepatocellular carcinoma, possibly through inhibition ofBcl-2family proteins. J Hepatol2006;44(6):1074-82.
41Wu T. Cyclooxygenase-2in hepatocellular carcinoma. Cancer Treat Rev.2006;32(1):28-44.
42Cheng AS, Chan HL, To KF, Leung WK, Chan KK, Liew CT, Sung JJ.Cyclooxygenase-2pathway correlates with vascular endothelial growth factorexpression and tumor angiogenesis in hepatitis B virus-associatedhepatocellular carcinoma. Int J Oncol2004;24(4):853-60.
43Koga H, Sakisaka S, Ohishi M, Kawaguchi T, Taniguchi E, Sasatomi K,Harada M, Kusaba T, Tanaka M, Kimura R, Nakashima Y, Nakashima O,Kojiro M, Kurohiji T, Sata M. Expression of cyclooxygenase-2in humanhepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology1999;29(3):688-96.
44Fernández-Martínez A, Mollá B, Mayoral R, Boscá L, Casado M, Martín-SanzP. Cyclo-oxygenase2expression impairs serum-withdrawal-induced apoptosisin liver cells. Biochem J2006;398(3):371-80.
45Li T, Yang Y,, Hua X, Wang G, Liu W, Jia C, Tai Y, Zhang Q, Chen G.Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunctionvia PGE2and IDO. Cancer Lett2012;318(2):154-61.
46Mayoral R, Fernández-Martínez A, Boscá L, Martín-Sanz P. Prostaglandin E2promotes migration and adhesion in hepatocellular carcinoma cells.Carcinogenesis2005;26(4):753-61.
47徐晓丽;李刘.喉癌手术前后血浆前列腺素E-2水平变化及临床意义.临床耳鼻咽喉科杂志2000;14(3):106-07.
48Cordes T, Hoellen F, Dittmer C, Salehin D, Kümmel S, Friedrich M, K ster F,Becker S, Diedrich K, Thill M. Correlation of prostaglandin metabolizingenzymes and serum PGE2levels with vitamin D receptor and serum25(OH)2D3levels in breast and ovarian cancer. Anticancer Res2012;32(1):351-7.
49Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP.Long-term effect of aspirin on colorectal cancer incidence and mortality:20-year follow-up of five randomised trials. Lancet Infect Dis2010;376(9754):1741–50.
50Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW.Effect of daily aspirin on long-term risk of death due to cancer: analysis ofindividual patient data from randomised trials. Lancet2011;377(9759):31-41.
51金娟，何义富，魏伟.肝细胞癌PGE2受体的信号转导通路及其可能药物作用靶点.中国新药杂志2008;17(7):1470-73.
52Fitzgerald GA. Coxibs and cardiovascular disease. N Engl J Med2004;351(17):1709-11.
53Jones SC. Relative thromboembolic risks associated with COX-2inhibitors.Ann Pharmacother2005;39(7-8):1249-59.
54Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K,Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA;Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators.Cardiovascular events associated with rofecoxib in a colorectal adenomachemoprevention trial. N Engl J Med2005;352(11):1092-102.
55Chen XL, Wang Q, Cao LQ, Huang XH, Fu XH, Tan HX, Zhen MC, Chen JS.Epigallocatechin-3-gallate induces apoptosis in human hepatocellularcarcinoma cells. Zhonghua Yi Xue Za Zhi2008;88(36):2524-8.
56Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenicswitch during tumorigenesis. cell1996;86(3):353-64.
1Calvisi DF, Ladu S, Gorden A, Farina M, Lee JS, Conner EA,Schroeder I, Factor VM, Thorgeirsson SS.. Mechanistic and prognosticsignificance of aberrant methylation in the molecular pathogenesis of humanhepatocellular carcinoma. J Clin Invest2007;117(9):2713–22.
2Breinig M, Rieker R, Eiteneuer E, Wertenbruch T, Haugg AM, Helmke BM,Schirmacher P, Kern MA. Differential expression of E-prostanoid receptors inhuman hepatocellular carcinoma. Int J Cancer2008;122(3):547-57.
3Mohammed NA, Abd El-Aleem SA,, El-Hafiz HA, McMahon RF.Distribution of constitutive (cox-1) and inducible (cox-2) cyclooxygenase inpostviral human liver cirrhosis: a possible role for cox-2in the pathogenesis ofliver cirrhosis. J Clin Pathol2004(4);57:350-54.
4Gridley G, McLaughlin JK, Ekbom A, Klareskog L, Adami HO, Hacker DG,Hoover R, Fraumeni JF Jr. Incidence of cancer among patients withrheumatoid arthritis. J Natl Cancer Inst1993;85(4):307-11.
5Koga H, Sakisaka S, Ohishi M, Kawaguchi T, Taniguchi E, Sasatomi K,Harada M, Kusaba T, Tanaka M, Kimura R, Nakashima Y, Nakashima O,Kojiro M, Kurohiji T, Sata M. Expression of cyclooxygenase-2in humanhepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology1999;29(3):688–96.
6Fernández-Martínez A, Mollá B, Mayoral R, Boscá L, Casado M, Martín-SanzP. Cyclo-oxygenase2expression impairs serum-withdrawal-induced apoptosisin liver cells. Biochem J2006;398(3):371-80.
7Leng J, Han C, Demetris AJ, Michalopoulos GK, Wu T. Cyclooxygenase-2promotes hepatocellular carcinoma cell growth through Akt activation:evidence for Akt inhibition in celecoxib-induced apoptosis. Hepatology2003;38(3):756–68.
8Rahman MA, Dhar DK, Yamaguchi E, Maruyama S, Sato T, Hayashi H, OnoT, Yamanoi A, Kohno H, Nagasue N. Coexpression of inducible nitric oxidesynthase and COX-2in hepatocellular carcinoma and surrounding liver:possible involvement of COX-2in the angiogenesis of hepatitis Cvirus-positive cases. Clin Cancer Res2001;7(5):1325-32.
9Kern MA, Haugg AM, Koch AF, Schilling T, Breuhahn K, Walczak H,Fleischer B, Trautwein C, Michalski C, Schulze-Bergkamen H, Friess H,Stremmel W, Krammer PH, Schirmacher P, Müller M. Cyclooxygenase-2inhibition induces apoptosis signaling via death receptors and mitochondria inhepatocellular carcinoma. Cancer Res2006;66(14):7059-66.
10Kern MA, Sch neweiss MM, Sahi D, Bahlo M, Haugg AM, Kasper HU,Dienes HP, K ferstein H, Breuhahn K, Schirmacher P. Cyclooxygenase-2inhibitors suppress the growth of human hepatocellular carcinoma implants innude mice. Carcinogenesis2004;25(7):1193-9.
11Kern MA, Schubert D, Sahi D, Sch neweiss MM, Moll I, Haugg AM, DienesHP, Breuhahn K, Schirmacher P. Proapoptotic and antiproliferative potentialof selective cyclooxygenase-2inhibitors in human liver tumor cells.Hepatology2002;36(4Pt1):885-94.
12Bae SH, Jung ES, Park YM, Kim BS, Kim BK, Kim DG, Ryu WS. Expressionof cyclooxygenase-2(COX-2) in hepatocellular carcinoma and growthinhibition of hepatoma cell lines by a COX-2inhibitor, NS-398. Clin CancerRes2001;7(5):1410-18.
13Sung YK, Hwang SY, Kim JO, Bae HI, Kim JC, Kim MK. The correlationbetween cyclooxygenase-2expression and hepatocellular carcinogenesis. MolCells2004;17(1):35-8.
14Sanghi S, MacLaughlin EJ, Jewell CW, Chaffer S, Naus PJ, Watson LE,Dostal DE. Cyclooxygenase-2inhibitors: a painful lesson. CardiovascHematol Disord Drug Targets2006;6(2):85-100.
15Togo S, Chen H, Takahashi T, Kubota T, Matsuo K, Morioka D, Watanabe K,Yamamoto H, Nagashima Y, Shimada H. Prostaglandin E (1) ImprovesSurvival Rate After95%Hepatectomy in Rats. J Surg Res2007;146(1):66-72.
16张成平.前列腺素E的生物学效应及在肝脏病理生理作用.国外医学消化系统疾病分册1995;15(2):88-91.
17缪新权，鲁慎文，黄宜雄，李桂云，朱丽明. PGE1治疗慢性乙型肝炎51例.新消化病学杂志1995;3(2):107-08.
18Han C, Demetris AJ, Michalopoulos G, Shelhamer JH, Wu T.85-kDa cPLA(2)plays a critical role in P cription in human hepatoma cells. Am J PhysiolGastrointest Liver Physiol2002;282(4): G586-97.
19Williams CS, Mann M, DuBois RN. The role of cyclooxygenases ininflammation, cancer, and development. Oncogene1999;18(55):7908-16.
20Hagi A, Nakayama M, Miura Y, Yagasaki K. Effects of a fish oil-basedemulsion on rat hepatoma cell invasion in culture. Nutrition2007;23(11-12):871-7.
21朱东，叶蕾，朱肖鸿，严颖.前列腺素E1治疗高黄疸慢性乙型肝炎36例.浙江中西医结合杂志2005;15(7):439-40.
22徐启恒，曹红，周四海.前列腺素E1治疗慢性病毒性肝炎、肝硬化及重症肝炎的疗效.中国临床药学杂志1999;8(4):211-13.
23Chun KS, Akunda JK, Langenbach R. Cyclooxygenase-2inhibitsUVB-induced apoptosis in mouse skin by activating the prostaglandin E2receptors, EP2and EP4. Cancer Res2007;67(5):2015–21.
24Chu AJ, Chou TH, Chen BD. Prevention of colorectal cancer using COX-2inhibitors: basic science and clinical applications. Front Biosci2004;9:2697–713.
25Wu T, Leng J, Han C, Demetris AJ. The cyclooxygenase-2inhibitor celecoxibblocks phosphorylation of Akt and induces apoptosis in humancholangiocarcinoma cells. Mol Cancer Ther2004;3(3):299–307.
26Mutoh M, Takahashi M, Wakabayashi K. Roles of prostanoids in coloncarcinogenesis and their potential targeting for cancer chemoprevention. CurrPharm Des2006;12(19):2375–82.
27Wang D, Dubois RN. Cyclooxygenase-2: a potential target in breast cancer.Semin Oncol2004;31(1Suppl3):64–73.
28Greenhough A, Wallam CA，Greenhough A WC, Hicks DJ, Moorghen M,Williams AC, Paraskeva C. The proapoptotic BH3-only protein Bim isdownregulated in a subset of colorectal cancers and is repressed byantiapoptotic COX-2/PGE(2) signalling in colorectal adenoma cells.Oncogene2010;29(23):3398–410.
29Basu GD, Pathangey LB, Tinder TL, Lagioia M, Gendler SJ, Mukherjee P..Cyclooxygenase-2inhibitor induces apoptosis in breast cancer cells in an invivo model of spontaneous metastatic breast cancer. Mol Cancer Res2004;2(11):632–42.
30Strong VE, Winter J, Yan Z, Smyth GP, Mestre JR, Maddali S, Schaefer PA,Yurt RW, Stapleton PP, Daly JM. Prostaglandin E2receptors EP2and EP4aredown-regulated in human mononuclear cells after injury. Surgery2001;130(2):249-55.
31Han C, Michalopoulos GK, Wu T. Prostaglandin E2receptor EP1transactivates EGFR/MET receptor tyrosine kinases and enhancesinvasiveness in human hepatocellular carcinoma cells. J Cell Physiol2006;207(1):261-70.
32Kawamori T, Uchiya N, Nakatsugi S, Watanabe K, Ohuchida S, Yamamoto H,Maruyama T, Kondo K, Sugimura T, Wakabayashi K. Chemopreventiveeffects of ONO-8711, a selective prostaglandin E receptor EP(1) antagonist,on breast cancer development. Carcinogenesis2001;22(12):2001-4.
33Niho N, Mutoh M, Kitamura T, Takahashi M, Sato H, Yamamoto H,Maruyama T, Ohuchida S, Sugimura T, Wakabayashi K. Suppression ofazoxymethane-induced colon cancer development in rats by a prostaglandin Ereceptor EP1-selective antagonist. Cancer Sci2005;96(5):260-64.
34Bilson HA, Mitchell DL, Ashby B. Human prostaglandin EP3receptorisoforms show different agonist-induced internalization patterns. FEBS Lett2004;572(1-3):271-75.
35Yamaki T, Endoh K, Miyahara M, Nagamine I, Thi Thu Huong N, Sakurai H,Pokorny J, Yano T. Prostaglandin E2activates Src signaling in lungadenocarcinoma cell via EP3. Cancer Lett2004;214(1):115-20.
36Yano T, Zissel G, Muller-Qernheim J, Jae Shin S, Satoh H, Ichikawa T.Prostaglandin E2reinforces the activation of Ras signal pathway in lungadenocarcinoma cells via EP3. FEBS Lett2002;518(1-3):154-58.
37Shoji Y, Takahashi M, Kitamura T, Watanabe K, Kawamori T, Maruyama T,Sugimoto Y, Negishi M, Narumiya S, Sugimura T, Wakabayashi K.Downregulation of prostaglandin E receptor subtype EP3during colon cancerdevelopment. Gut2004;53(8):1151-58.
38Gómez-Hernández A, Martín-Ventura JL, Sánchez-Galán E, Vidal C, OrtegoM, Blanco-Colio LM, Ortega L, Tu ón J, Egido J. Overexpression of COX-2,Prostaglandin E synthase-1and prostaglandin E receptors in bloodmononuclear cells and plaque of patients with carotid atherosclerosis:regulation by nuclear factor-kappaB. Atherosclerosis2006;187(1):139-49.