食管鳞癌中HuR和VEGF-C的表达及意义
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摘要
目的
分析人食管鳞癌(ESCC)中HuR.VEGF-C的表达与患者临床病理特征及预后的关系,为筛选食管鳞癌新的治疗靶点提供实验依据,明确能否作为筛选早期食管鳞癌及淋巴结转移的生物学标记物。
方法
1、应用免疫组织化学染色(S-P法)检测58例人食管鳞癌组织和20例癌旁正常组织中HuR.VEGF-C的表达,分析二者之间的相关性及其与临床病理特征的关系。
2、采用Kaplan-Meier法和Cox比例风险回归模型,分析HuR.VEGF-C的表达与术后生存的关系。
3、应用ELISA法检测58例食管鳞癌患者及20例正常健康志愿者血清中VEGF-C水平,分析其与临床病理参数的关系。
结果
1、58例ESCC组织中,HuR胞浆阳性表达率、HuR胞核阳性表达率、VEGF-C阳性表达率分别为46.55%(27/58)、75.86%(44/58)和68.97%(40/58),与正常对照组的0%、3.45%和15.00%比较差异均有显著的统计学意义(P<0.01)。胞浆HuR.VEGF-C的表达与ESCC患者的淋巴结转移、肿瘤浸润深度和TNM分期均有显著的相关性(P<0.05)。胞浆HuR表达还与肿瘤大小有关(P<0.05)。胞核HuR表达与ESCC患者所有的临床病理特征均无相关性；
2、食管鳞癌中胞浆HuR.VEGF-C的表达水平间存在明显的等级正相关性(r=0.351,P<0.05)；
3、胞浆HuR阳性表达组的5年生存率明显低于阴性表达组(P<0.05)；胞核HuR阳性表达组的5年生存率虽然低于阴性表达组,但无统计学意义；VEGF-C阳性表达组的5年生存率明显低于阴性表达组(P<0.05)；胞浆HuR、VEGF-C双阳性表达组的5年生存率明显低,于双阴性表达组(P<0.05)；Cox回归模型的多变量分析结果显示,食管鳞癌患者预后的独立危险因素包括胞浆HuR表达(RR=2.344：95%C1,1.140-4.820；P=0.021)、VEGF-C表达(RR=2.565：95%Cl,1.087-6.052；P=0.032)以及淋巴结的转移(RR=2.233；95%Cl,1.068-4.668；P=0.033),而与胞核HuR的表达及其他临床病理特征均无相关性(P>0.05)
4、58例ESCC患者与20例正常健康志愿者者血青VEGF-C表达水平分别为(643.58±144.56)pg/ml和(542.74±117.55)pg/ml,二者比较,差异具有显著的统计学意义(P<0.01)。Ⅲ、Ⅳ期患者血清VEGF-C的浓度(665.51±141.20)pg/ml和Ⅰ、Ⅱ期患者血清VEGF-C的浓度(574.66±137.61)pg/ml之间存在统计学上显著的差异(P<0.05)；有淋巴结转移的ESCC患者血清VEGF-C水平(685.51±142.52)pg/ml显著高于无淋巴结转移的ESCC患者的血.清VEGF-C水平(601.65±136.34)pg/ml(P<0.05)；与肿瘤浸润未超过外膜(T1+T2)的患者血清VEGF-C的水平为(576.01±140.96)pg/ml相比,肿瘤浸润超过外膜(T3+T4)的患者血清VEGF-C的水平(669.33士139.00)pg/ml显著升高。上述结果提示ESCC患者血清中VEGF-C表达水平与TNM分期(P<0.05)、淋巴结转移(P<0.05)以及肿瘤浸润深度(P<0.05)均有显著相关性。
结论
ESCC组织中HuR、VEGF-C表达和外周血VEGF-C水平与肿瘤进展、淋巴结转移密切相关,是ESCC的不良预后因子,可作为潜在的抗肿瘤靶点。
Objective
Study the expression of HuR and VEGF-C in Esophageal Squamous Cell Carcinoma (ESCC), and correlate results with patients'clinicopathological parameters and survival for providing experimental basis to screen new target for the treatment of ESCC, assessing their usefulness as biological markers for determining early ESCC and lymph node metastasis.
Methods
1. The expression of HuR and VEGF-C in 58 ESCC tissues and 20 control paracancerous normal tissues were detected by immunohistochemistry staining S-P assay. The correlation between the expression of HuR and VEGF-C and the clinicalpathological parameters and the relationship between the expression of HuR and VEGF-C were analyzed.
2. The correlation between HuR and VEGF-C expression and patient outcome was determined by Kaplan-Meier method and Cox proportional hazards regression model.
3. Serum VEGF-C levels in 58 patients with ESCC and 20 healthy people were measured by ELISA assay, and the relationships between VEGF-C and different clinicopathological factors was analyzed.
Results
1. In 58 ESCC tissues, positive rate of cytoplasmic HuR, nuclear HuR and VEGF-C were 46.55%(27/58),75.86%(44/58) and 68.97%(40/58), respectively. Compared With positive rate of cytoplasmic HuR, nuclear HuR and VEGF-C in normal Esophagal tissues,0%(0/20),10.00%(2/20)and 15.00%(3/20) respective-ely,the difference had a statistic significance (P<0.01). Both the expression of cytoplasmic HuR protein and VEGF-C protein were positively correlated with lymph node metastasis, depth of tumor invasion and TNM stages (P<0.05). In addition, the expression of cytoplasmic HuR protein was positively correlated with tumor size. However, the expression of nuclear HuR protein was not correlated with any clinicopathological factors.
2. There was an obvious positive correlation between the expression of cytoplasmic HuR and VEGF-C (r=0.351, P<0.05).
3. The follow-up visit in the patients showed that five-year survival rate was greatly lower in the positive expression of the cytoplasmic HuR group than that in the negative group (P<0.05). Although the positive expression of nuclear HuR group had a lower 5 year survival rate than the negative group, there is no statistic significance. Meanwhile, the positive expression of VEGF-C group had a lower 5 year survival rate than the negative group obviously (P<0.05). The 5 year survival rate in the cytoplasmic HuR and VEGF-C double positive group was lower than the double negative group obviously. In multivariate analysis using the Cox regression model, the independent prognostic parameters for ESCC patients included cytoplasmic HuR express(RR=2.344; 95% Cl,1.140-4.820;P=0.021), VEGF-C express (RR=2.565; 95% Cl,1.087-6.052;P=0.032) and lymph node metastasis (RR=2.233; 95% Cl,1.068-4.668; P=0.033), had no correlation with nuclear HuR express and other clinicopathological characteristics (?>0.05)。
4. We found that the serum VEGF-C level in 58 ESCC patients and 20 healthy controls was (643.58±144.56) pg/ml, (542.74±117.55) pg/ml, respectiv-ely,indicated an obvious statistic difference (P<0.01). The concentrations of VEGF-C were statistically significantly different in stage III and stage IV ESCC patients (665.51±141.20) pg/ml and stage I and stageⅡESCC patients (574.66±137.61) pg/ml (P<0.05). ESCC patients with lymph node metastasis had a higher VEGF-C level (685.51±142.52) pg/ml than those without lymph node metastasis (601.65±136.34) pg/ml (P<0.05).Compared with serum VEGF-C concentration (576.01±140.96) pg/m in patients whose depth of tumor invasion did not overpass serous membrane (T1+T2), serum VEGF-C concentration (576.01±140.96) pg/m in patients whose depth of tumor invasion overpassed serous membrane (T3+T4) elevated notably. Above-mentioned results suggested that Serum VEGF-C level in ESCC patients was closely correlated with TNM stage (?<0.05), lymph node metastasis (P<0.05) and depth of tumor invasion (P<0.05).
Conclusion
Both the expression of HuR and VEGF-C in ESCC tissues and VEGF-C level in peripheral blood are closely correlated with malignant tumor progress and lymph nodes metastasis.Therefore, they are considered as poor prognosis markers of ESCC, become potential anti-tumor therapeutic targets.
分析人食管鳞癌(ESCC)中HuR.VEGF-C的表达与患者临床病理特征及预后的关系,为筛选食管鳞癌新的治疗靶点提供实验依据,明确能否作为筛选早期食管鳞癌及淋巴结转移的生物学标记物。
方法
1、应用免疫组织化学染色(S-P法)检测58例人食管鳞癌组织和20例癌旁正常组织中HuR.VEGF-C的表达,分析二者之间的相关性及其与临床病理特征的关系。
2、采用Kaplan-Meier法和Cox比例风险回归模型,分析HuR.VEGF-C的表达与术后生存的关系。
3、应用ELISA法检测58例食管鳞癌患者及20例正常健康志愿者血清中VEGF-C水平,分析其与临床病理参数的关系。
结果
1、58例ESCC组织中,HuR胞浆阳性表达率、HuR胞核阳性表达率、VEGF-C阳性表达率分别为46.55%(27/58)、75.86%(44/58)和68.97%(40/58),与正常对照组的0%、3.45%和15.00%比较差异均有显著的统计学意义(P<0.01)。胞浆HuR.VEGF-C的表达与ESCC患者的淋巴结转移、肿瘤浸润深度和TNM分期均有显著的相关性(P<0.05)。胞浆HuR表达还与肿瘤大小有关(P<0.05)。胞核HuR表达与ESCC患者所有的临床病理特征均无相关性；
2、食管鳞癌中胞浆HuR.VEGF-C的表达水平间存在明显的等级正相关性(r=0.351,P<0.05)；
3、胞浆HuR阳性表达组的5年生存率明显低于阴性表达组(P<0.05)；胞核HuR阳性表达组的5年生存率虽然低于阴性表达组,但无统计学意义；VEGF-C阳性表达组的5年生存率明显低于阴性表达组(P<0.05)；胞浆HuR、VEGF-C双阳性表达组的5年生存率明显低,于双阴性表达组(P<0.05)；Cox回归模型的多变量分析结果显示,食管鳞癌患者预后的独立危险因素包括胞浆HuR表达(RR=2.344：95%C1,1.140-4.820；P=0.021)、VEGF-C表达(RR=2.565：95%Cl,1.087-6.052；P=0.032)以及淋巴结的转移(RR=2.233；95%Cl,1.068-4.668；P=0.033),而与胞核HuR的表达及其他临床病理特征均无相关性(P>0.05)
4、58例ESCC患者与20例正常健康志愿者者血青VEGF-C表达水平分别为(643.58±144.56)pg/ml和(542.74±117.55)pg/ml,二者比较,差异具有显著的统计学意义(P<0.01)。Ⅲ、Ⅳ期患者血清VEGF-C的浓度(665.51±141.20)pg/ml和Ⅰ、Ⅱ期患者血清VEGF-C的浓度(574.66±137.61)pg/ml之间存在统计学上显著的差异(P<0.05)；有淋巴结转移的ESCC患者血清VEGF-C水平(685.51±142.52)pg/ml显著高于无淋巴结转移的ESCC患者的血.清VEGF-C水平(601.65±136.34)pg/ml(P<0.05)；与肿瘤浸润未超过外膜(T1+T2)的患者血清VEGF-C的水平为(576.01±140.96)pg/ml相比,肿瘤浸润超过外膜(T3+T4)的患者血清VEGF-C的水平(669.33士139.00)pg/ml显著升高。上述结果提示ESCC患者血清中VEGF-C表达水平与TNM分期(P<0.05)、淋巴结转移(P<0.05)以及肿瘤浸润深度(P<0.05)均有显著相关性。
结论
ESCC组织中HuR、VEGF-C表达和外周血VEGF-C水平与肿瘤进展、淋巴结转移密切相关,是ESCC的不良预后因子,可作为潜在的抗肿瘤靶点。
Objective
Study the expression of HuR and VEGF-C in Esophageal Squamous Cell Carcinoma (ESCC), and correlate results with patients'clinicopathological parameters and survival for providing experimental basis to screen new target for the treatment of ESCC, assessing their usefulness as biological markers for determining early ESCC and lymph node metastasis.
Methods
1. The expression of HuR and VEGF-C in 58 ESCC tissues and 20 control paracancerous normal tissues were detected by immunohistochemistry staining S-P assay. The correlation between the expression of HuR and VEGF-C and the clinicalpathological parameters and the relationship between the expression of HuR and VEGF-C were analyzed.
2. The correlation between HuR and VEGF-C expression and patient outcome was determined by Kaplan-Meier method and Cox proportional hazards regression model.
3. Serum VEGF-C levels in 58 patients with ESCC and 20 healthy people were measured by ELISA assay, and the relationships between VEGF-C and different clinicopathological factors was analyzed.
Results
1. In 58 ESCC tissues, positive rate of cytoplasmic HuR, nuclear HuR and VEGF-C were 46.55%(27/58),75.86%(44/58) and 68.97%(40/58), respectively. Compared With positive rate of cytoplasmic HuR, nuclear HuR and VEGF-C in normal Esophagal tissues,0%(0/20),10.00%(2/20)and 15.00%(3/20) respective-ely,the difference had a statistic significance (P<0.01). Both the expression of cytoplasmic HuR protein and VEGF-C protein were positively correlated with lymph node metastasis, depth of tumor invasion and TNM stages (P<0.05). In addition, the expression of cytoplasmic HuR protein was positively correlated with tumor size. However, the expression of nuclear HuR protein was not correlated with any clinicopathological factors.
2. There was an obvious positive correlation between the expression of cytoplasmic HuR and VEGF-C (r=0.351, P<0.05).
3. The follow-up visit in the patients showed that five-year survival rate was greatly lower in the positive expression of the cytoplasmic HuR group than that in the negative group (P<0.05). Although the positive expression of nuclear HuR group had a lower 5 year survival rate than the negative group, there is no statistic significance. Meanwhile, the positive expression of VEGF-C group had a lower 5 year survival rate than the negative group obviously (P<0.05). The 5 year survival rate in the cytoplasmic HuR and VEGF-C double positive group was lower than the double negative group obviously. In multivariate analysis using the Cox regression model, the independent prognostic parameters for ESCC patients included cytoplasmic HuR express(RR=2.344; 95% Cl,1.140-4.820;P=0.021), VEGF-C express (RR=2.565; 95% Cl,1.087-6.052;P=0.032) and lymph node metastasis (RR=2.233; 95% Cl,1.068-4.668; P=0.033), had no correlation with nuclear HuR express and other clinicopathological characteristics (?>0.05)。
4. We found that the serum VEGF-C level in 58 ESCC patients and 20 healthy controls was (643.58±144.56) pg/ml, (542.74±117.55) pg/ml, respectiv-ely,indicated an obvious statistic difference (P<0.01). The concentrations of VEGF-C were statistically significantly different in stage III and stage IV ESCC patients (665.51±141.20) pg/ml and stage I and stageⅡESCC patients (574.66±137.61) pg/ml (P<0.05). ESCC patients with lymph node metastasis had a higher VEGF-C level (685.51±142.52) pg/ml than those without lymph node metastasis (601.65±136.34) pg/ml (P<0.05).Compared with serum VEGF-C concentration (576.01±140.96) pg/m in patients whose depth of tumor invasion did not overpass serous membrane (T1+T2), serum VEGF-C concentration (576.01±140.96) pg/m in patients whose depth of tumor invasion overpassed serous membrane (T3+T4) elevated notably. Above-mentioned results suggested that Serum VEGF-C level in ESCC patients was closely correlated with TNM stage (?<0.05), lymph node metastasis (P<0.05) and depth of tumor invasion (P<0.05).
Conclusion
Both the expression of HuR and VEGF-C in ESCC tissues and VEGF-C level in peripheral blood are closely correlated with malignant tumor progress and lymph nodes metastasis.Therefore, they are considered as poor prognosis markers of ESCC, become potential anti-tumor therapeutic targets.
引文
[1]Joory KD, Levick JR, Mortimer PS, et al. Vascular endothelial growth factor-C (VEGF-C) expression in normal human tissues. Lymphat Res Biol,2006,4(2):73-82.
[2]Su JL, Yang PC, Shih JY, et al. The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells.Cancer Cell,2006,9(3):209-23.
[3]Staker SA, Achen MG, Jussila L, et al. Lymphangiogenesis and cancermetastasis.Nat Rev Cancer,2002,2 (8):573-8.
[4]Benjamin D and Moroni C. mRNA stability and cancer:an emerging link? Expert Opin Biol Ther,2007,7(10):1515-29.
[5]Espel E. The role of the AU-rich elements of mRNAs in controlling translation.Semin Cell Dev Biol,2005,16(1):59-67.
[6]Wang JG, CollingeM, Ramgolam V, et al.LFA 1 dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation. J Immunol,2006,76 (4):2105.
[7]Wang W, Caldwell MC, Lin S, et al.HuR regulates cyclinA and cyclinB1 mRNA stability during cell proliferation.E MBO J,2000,19(10):2340.
[8]Ulus Atasoy, Stephanie L, Curry Isabel, et al. Regulation of Eotaxin Gene expression by TNF-α and IL-4 through mRNA stabilization:involvement of the RNA-binding protein HuR.J Immunol,2003,171 (10):4369-78.
[9]Levy N, Chung S, Furneaux H, et al.Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. Biol Chem,1998, 273:417-23.
[10]Sengup ta S, JangBC, WuMT, et al. The RNA-binding protein HuR regulates the exp ression of cyclooxygenase-2. J Biol Chem,2003,278 (27):25227-33.
[11]Heinonen M, Fagerholm R, Aaltonen K, et al.Prognostic role of HuR in hereditary breast cancer.Clin Cancer Res,2007,13(23):6959-63.
[12]Chilov D, Kukk E, Taira S, et al.Genomic organization of human and mouse genes for vascular endothelial growth factor C.J Biol Chem,1997,272(40):25176-83.
[13]Heinonen M, Bono P, Narko K, et al. Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma.Cancer Res,2005,65 (6):2157-61.
[14]Mrena J, Wiksten J, Thiel A, et al. Cyclooxygenase-2 Is an Independent Prognostic Factor in Gastric Cancer and Its Expression Is Regulated by the Messenger RNA Stability Factor HuR. Clin Cancer Res,2005,11(20):7362-8.
[15]Denkert C, Weichert W, Pest S, et al. Overexpression of the Embryonic-Lethal Abnormal Vision-like Protein HuR in Ovarian Carcinoma Is a Prognostic Factor and Is Associated with Increased Cyclooxygenase 2 Expression. Cancer Research,2004, 1(64):189-195.
[16]Wang J, Zhao Wp, Guo Y,et al. The Expression of RNA-Binding Protein HuR in Non-Small Cell Lung Cancer Correlates with Vascular Endothelial Growth Factor-C Expression and Lymph Node Metastasis. Oncology,2009,76:420-9.
[17]Tamura M, Oda M, Tsunezuka Y, et al. Chest CT and serum vascular endothelial growth factor-C level to diagnose lymph node metastasis in patients with primary non-small cell lung cancer. Clinical Inv,2004,126 (2):342-6.
[18]Greene FL, Compton CC, Fritz AG, et al. AJCC Cancer Staging Atlas. New York: Sp-ringer,2006,77-88.
[19]刘巍,郝希山,陈勇等.1526例胸段食管癌及贲门癌淋巴结转移状况分析[J].中国肿瘤临床,2008,35(1)：601-05.
[20]Takizawa H, Kondo K, Fujino H, et al. The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer. Br J Cancer,2006,95(1):75-9.
[21]Antic D, Keene JD. Embryonic lethal abnormal visual RNA-binding proteins involved in growth, differentiation, and posttranscriptional geneexpression. Am J Hum Genet, 1997,61:273-8.
[22]Lopez de Silanes I, Fan J, Yang X, et al. Role of the RNA-binding protein HuR in colon carcinogenesis.Oncogene,2003,22:7146-54.
[23]Gallouzi IE, Steitz JA. Protein ligandsmediate the CRM1-dependent export of HuR in response to heat shock. RNA,2003,9(11):1410.
[24]Zou T, Liu L, Rao JN, et al. Polyamines modulate the subcellular localization of RNA-binding p rotein HuR through AMP-activated protein kinase-regulated phosphoryl-ation and acetylation of importin alphal. Biochem J,2008,409 (2):389-98.
[25]Erkinheimo TL, Lassus H, Sivula A, et al. Cytoplasmic HuR expression correlates w ith poor outcome and with cyclooxygenase-2 expression in serous ovarian carcinoma. Cancer Res,2003,63 (22):7591-5.
[26]Derry MC, Yanagiya A, Martineau Y, Sonenberg N. Regulation of poly (A)-binding protein through PABP-interacting proteins.Cold Spring Harb Symp Quant Biol,2006, 71:537-43.
[27]Chen CY, Gherzi R, Ong SE, et al.AU binding proteins recruit the exosome to degrade ARE-containing mRNAs.Cell,2001,107(4):451-64.
[28]Luo H, Li J, Yang T, et al. Expression and significance of VEGF-C and VEGF-D in differentiated thyroid carcinoma. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2009,23(12):531-4.
[29]Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is requ-ired for sprouting of the first lymphatic vessels from embryonic veins.Nat Immunol,2004,5(1):74-80
[30]Furudoi A, Tanaka S, Haruma K, et al.Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma.Oncology,2002,62(2):157-66.
[31]Xie XD, Qu SX, Zheng ZD, et al.Relation of lymphatic microvessel density detected by monoclonal antibody D2-40 with VEGF-C expression in breast cancer. Zhonghua ZhongLiu Za Zhi,2008,30(5):356-60.
[32]Tsutsumi S, Kuwao H, Snimura T, et al.Vascular endothelial growth factor-C (VEGF-C) expression in PT2 gastric cancer. Hepatogastroenterology,2005,52:629-32.
[33]Liu P, Chen W, Zhu H, Liu B, et al. Expression of VEGF-C correlates with a poor prognosis based on analysis of prognostic factors in 73 patients with esophageal squamous cell carcinomas.Jpn J Clin Oncol.2009,39(10):644-50.
[34]Kitadai Y, Amioka T, Haruma K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Int J Cancer,2001,93 (5):662-6.
[35]Byeon J S, J ung HY, Lee YJ, et al. Clinicopathological significance of vascular endothelial growth factor-C and cyclooxygenase-2 in esophageal squamous cell carcinoma.Gastroenterol Hepatol,2004,19 (6):648-54.
[36]Noguchi T, Takeno S, Shibata T, et al. VEGF-C expression correlates with histolo-gical differentiation and metastasis in squamous cell car-cinoma of the esophagus. Oncol Rep,2002,9 (5):995-9.
[37]Pan XF, Bao GL, Fang WT, et al. VEGF-C mRNA expression and its relationship with clinicopathological parameters in ESCC. Clin J Oncol,2008,30(6):437-40.
[38]Do S, Araujo ES, Kalil RK, et al. Expression of embryonic lethal abnormal vision (ELAV)-like protein HuR and cyclooxygenase-2(COX-2) in Ewing sarcoma. Tumori, 2008,94:347-50.
[39]Niesporek S, Kristiansen G, Thoma A, et al. Expression of the ELAV-like protein HuR in human prostate carcinoma is an indicator of disease relapse and linked to COX-2 expression. International Journal of Oncology,2008,32:341-7.
[40]Yoo PS, Mulkeen AL, Cha CH. Posttranscrip tional regulation of vascular endothelial growth factor:imp lications for tumor angiogenesis. World J Gastroenterol,2006,12 (31):4937-42.
[41]Sengup ta S, Jang BC, W u M T, et al. The RNA-binding protein HuR regulates the expression of cyclooxygenase-2. J Biol Chem,2003,278 (27):25227-33.
[42]Lim SJ, Kim H I, Kim JY, et al. Expression of HuR is associated with increased cyclooxygenase-2 expression in uterine cervical carcinoma. Int J Gynecol Pathol, 2007,26 (3):229-34.
[43]Tamura M, Ohta Y.Serum vascular endothelial growth factor-C level in patients with primary monsmall cell lung carcinoma.A possible diagnostic tool for lymph node metastasis.Cancer,2003,98:1217-22.
[44]Tamura M, Oda M, Matsumoto I, et al.The combination assay with circulating vascular endothelial growth factor (VEGF)-C, matrix metalloprote-inase-9, and VEGF for diagnosing lymph node metastasis in patients with non-small cell lung cancer. Ann Surg Oncol.2004, 11(10):928-33.
[45]Mitsuhashi A, Suzuka K, Yamazawa K,Cancer, etal,Serum vascular endothelial growth factor (VEGF) and VEGF-C levels as tumor markers in patients with cervical carcinoma.2005,103(4):724-30.
[46]Mathur SP, Mathur RS, Gray EA, etal. Serum vascular endothelial growth factor C (VEGF-C) as a specific biomarker for advanced cervical cancer:Relationship to insulin-like growth factor II (IGF-Ⅱ), IGF binding protein 3 (IGF-BP3) and VEGF-A [corrected] Gynecol Oncol.2005 Sep; 98(3):467-83
[47]Alabi AA, Suppiah A, Madden LA, et al. Preoperative serum levels of serum VEGF-C is associated with distant metastasis in colorectal cancer patients. Int J Colorectal Dis. 2009,24(3):269-74.
[48]Xu T, Chen D. Serum vascular endothelial growth factor-C and vascular endothelial growth factor level in patients with colorectal carcinoma and clinical significance. Journal of HuazhongUniversity of Science and Technology,2006,26:329-331
[49]Krzystek-Korpacka M, Matusiewicz M, Diakowska D, etal. Up-regulation of VEGF-C secreted by cancer cells and not VEGF-A correlates with clinical evaluation of lymph node metastasis in esophageal squamous cell carcinoma (ESCC). Cancer Lett,2007, 249(2):171-7.
[50]Kozlowski M, Kowalczuk O, Milewski R, et al.Serum vascular endothelial growth factors C and D in patients with oesophageal cancer.Eur J Cardiothorac Surg.2010, Mar 10.
[51]Giessen K, Di-Marco S, Clair E, et al. RNA-mediated HuR depletion leads to the inhibition of muscle cell differentiation.J Biol Chem,2003,47:47119-28.
[52]李勇,杨进强,赵增仁等.’VEGF-C反义寡核苷酸抑制人胃癌裸鼠移植瘤淋巴管生成的实验研究[J].中国肿瘤临床,2007,34(8)：437-40。
[1]Su JL, Yang PC, Shih JY,et al.The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells.Cancer Cell,2006,9(3):209-23.
[2]Takizawa H, Kondo K, Fujino H, et al. The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer. Br J Cancer, 2006,95(1):75-79.
[3]Staker SA, Achen MG, Jussila L, et al. Lymphangiogenesis and Cancer Metastasis. Nat Rev Cancer,2002,2 (8):573-78.
[4]Wang JG, Collinge M, Ramgolam V, et al.LFA 1 dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation. J Immunol,2006,76 (4):2105.
[5]Wang W, Caldwell MC, Lin S, et al. HuR regulates cyclinA and cyclinBl mRNA stability during cell proliferation.E MBO J,2000,19(10):2340.
[6]Ulus A, Stephanie L, Curry I,et al. Regulation of Eotaxin Gene expression by TNF-a and IL-4 through mRNA stabilization:, involvement of the RNA-binding proteinHuR.J Immunol,2003,171 (10):4369-78.
[7]Levy N, Chung S, Furneaux H, et al. Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. Biol Chem,1998,273(11): 6417-23.
[8]Sengup ta S, JangBC, WuMT, et al. The RNA-binding protein HuR regulates the expr-ession of cyclooxygenase-2. J Biol Chem,2003,278 (27):25227-33.
[9]Wang J, Zhao Wp, Guo Y,et al. The Expression of RNA-Binding Protein HuR in Non-Small Cell Lung Cancer Correlates with Vascular Endothelial Growth Factor-C Expression and Lymph Node Metastasis. Oncology,2009,76:420-29.
[10]Su JL, Shih JY, YenML, et al. Cyclooxygenase-2 induces EP1-and HER-2/Neu-dependent vascular endothelial growth factor-C upregulation:a novelmechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res,2004,64 (2):554-64.
[11]Timoshenko AV, Chakraborty C, Wagner GF, et al. COX-2 mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. Br J Cancer,2006,94 (8):1154-63.
[12]Katsuta M, Miyashita M, Makinoa H, et al. Correlation of hypoxia inducible factor-la with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer. Exp Mol Pathol,2005,78 (2):123-30.
[13]Chang LK, Garcia CG, Farnebo F, et al. Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA,2004,101 (32):11658-63.
[14]Cao R, BjorndahlMA, Religa P, et al. PDGF-BB induces intratumoral lymphangio-genesis and promotes lymphatic metastasis. Cancer Cell,2004,6 (4):333-45.
[15]Morisada T,Oike Y,Yamada Y,et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood,2005,105 (12):4649-56.
[16]RistimakiA,Narko K,Enholm B,et al. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endo-thelial growth factor-C. J Biol Chem,1998,273 (14):8413-18.
[17]Subhojit Roy, Albert Chu, John Q, et al. D2-40 a novel monoclonal antibody against theM2A antigen as a marker to distinguish hemangiobla-stomas from renal cell carcinomas. Acta Neuropathol (Berl),2005,109 (5):497-502.
[18]Fukunaga M. Expression of D2-40 in lymphatic endothelium of normaltissues and in vascular tumours. Histopathology,2005,46(4):396-402.
[19]Saad RS, Lindner JL, Liu Y, et al. Lymphatic vessel density as prognostic marker in esophageal adenocarcinoma. Am J Clin Pathol,2009,131(1):92-8.
[20]Kitadai Y, Amioka T, Haruma K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Int J Cancer,2001,93 (5):662-66.
[21]Byeon JS, J ung HY, Lee YJ, et al. Clinicopathological significance of vascular endothelial growth factor-C and cyclooxygenase-2 in esophageal squamous cell carcinoma.Gastroenterol Hepatol,2004,19 (6):648-54.
[22]Tzao Ching, Lee SC, Tung HJ, et al. Expression of hypoxia-inducible factor (HIF)-la and vascular endothelial growth factor (VEGF)-D as outcome predictors in resected esophageal squamous cell carcinoma.Disease Markers,2008, (25) 141-48.
[23]Noguchi T,Takeno S,Shibata T,et al.VEGF-C expression correlates with histological differentiation and metastasis in squamous cell carcinoma of the esophagus. Oncol Rep,2002,9 (5):995-99.
[24]Pan XF, Bao GL, Fang WT,et al.VEGF-C mRNA expression and its relationship with clinicopathological parameters in ESCC. Clin J Oncol,2008,30(6):437-40.
[25]刘巍,郝希山,陈勇等.1526例胸段食管癌及贲门癌淋巴结转移状况分析[J].中国肿瘤临床,2008,35(1)：601-05.
[26]Mrena J, Wiksten J, Thiel A, et al. Cyclooxygenase-2 Is an Independent Prognostic Factor in Gastric Cancer and Its Expression Is Regulated by the Messenger RNA Stability Factor HuR. Clin Cancer Res,2005,11(20):7362-68.
[2]Su JL, Yang PC, Shih JY, et al. The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells.Cancer Cell,2006,9(3):209-23.
[3]Staker SA, Achen MG, Jussila L, et al. Lymphangiogenesis and cancermetastasis.Nat Rev Cancer,2002,2 (8):573-8.
[4]Benjamin D and Moroni C. mRNA stability and cancer:an emerging link? Expert Opin Biol Ther,2007,7(10):1515-29.
[5]Espel E. The role of the AU-rich elements of mRNAs in controlling translation.Semin Cell Dev Biol,2005,16(1):59-67.
[6]Wang JG, CollingeM, Ramgolam V, et al.LFA 1 dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation. J Immunol,2006,76 (4):2105.
[7]Wang W, Caldwell MC, Lin S, et al.HuR regulates cyclinA and cyclinB1 mRNA stability during cell proliferation.E MBO J,2000,19(10):2340.
[8]Ulus Atasoy, Stephanie L, Curry Isabel, et al. Regulation of Eotaxin Gene expression by TNF-α and IL-4 through mRNA stabilization:involvement of the RNA-binding protein HuR.J Immunol,2003,171 (10):4369-78.
[9]Levy N, Chung S, Furneaux H, et al.Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. Biol Chem,1998, 273:417-23.
[10]Sengup ta S, JangBC, WuMT, et al. The RNA-binding protein HuR regulates the exp ression of cyclooxygenase-2. J Biol Chem,2003,278 (27):25227-33.
[11]Heinonen M, Fagerholm R, Aaltonen K, et al.Prognostic role of HuR in hereditary breast cancer.Clin Cancer Res,2007,13(23):6959-63.
[12]Chilov D, Kukk E, Taira S, et al.Genomic organization of human and mouse genes for vascular endothelial growth factor C.J Biol Chem,1997,272(40):25176-83.
[13]Heinonen M, Bono P, Narko K, et al. Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma.Cancer Res,2005,65 (6):2157-61.
[14]Mrena J, Wiksten J, Thiel A, et al. Cyclooxygenase-2 Is an Independent Prognostic Factor in Gastric Cancer and Its Expression Is Regulated by the Messenger RNA Stability Factor HuR. Clin Cancer Res,2005,11(20):7362-8.
[15]Denkert C, Weichert W, Pest S, et al. Overexpression of the Embryonic-Lethal Abnormal Vision-like Protein HuR in Ovarian Carcinoma Is a Prognostic Factor and Is Associated with Increased Cyclooxygenase 2 Expression. Cancer Research,2004, 1(64):189-195.
[16]Wang J, Zhao Wp, Guo Y,et al. The Expression of RNA-Binding Protein HuR in Non-Small Cell Lung Cancer Correlates with Vascular Endothelial Growth Factor-C Expression and Lymph Node Metastasis. Oncology,2009,76:420-9.
[17]Tamura M, Oda M, Tsunezuka Y, et al. Chest CT and serum vascular endothelial growth factor-C level to diagnose lymph node metastasis in patients with primary non-small cell lung cancer. Clinical Inv,2004,126 (2):342-6.
[18]Greene FL, Compton CC, Fritz AG, et al. AJCC Cancer Staging Atlas. New York: Sp-ringer,2006,77-88.
[19]刘巍,郝希山,陈勇等.1526例胸段食管癌及贲门癌淋巴结转移状况分析[J].中国肿瘤临床,2008,35(1)：601-05.
[20]Takizawa H, Kondo K, Fujino H, et al. The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer. Br J Cancer,2006,95(1):75-9.
[21]Antic D, Keene JD. Embryonic lethal abnormal visual RNA-binding proteins involved in growth, differentiation, and posttranscriptional geneexpression. Am J Hum Genet, 1997,61:273-8.
[22]Lopez de Silanes I, Fan J, Yang X, et al. Role of the RNA-binding protein HuR in colon carcinogenesis.Oncogene,2003,22:7146-54.
[23]Gallouzi IE, Steitz JA. Protein ligandsmediate the CRM1-dependent export of HuR in response to heat shock. RNA,2003,9(11):1410.
[24]Zou T, Liu L, Rao JN, et al. Polyamines modulate the subcellular localization of RNA-binding p rotein HuR through AMP-activated protein kinase-regulated phosphoryl-ation and acetylation of importin alphal. Biochem J,2008,409 (2):389-98.
[25]Erkinheimo TL, Lassus H, Sivula A, et al. Cytoplasmic HuR expression correlates w ith poor outcome and with cyclooxygenase-2 expression in serous ovarian carcinoma. Cancer Res,2003,63 (22):7591-5.
[26]Derry MC, Yanagiya A, Martineau Y, Sonenberg N. Regulation of poly (A)-binding protein through PABP-interacting proteins.Cold Spring Harb Symp Quant Biol,2006, 71:537-43.
[27]Chen CY, Gherzi R, Ong SE, et al.AU binding proteins recruit the exosome to degrade ARE-containing mRNAs.Cell,2001,107(4):451-64.
[28]Luo H, Li J, Yang T, et al. Expression and significance of VEGF-C and VEGF-D in differentiated thyroid carcinoma. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2009,23(12):531-4.
[29]Karkkainen MJ, Haiko P, Sainio K, et al. Vascular endothelial growth factor C is requ-ired for sprouting of the first lymphatic vessels from embryonic veins.Nat Immunol,2004,5(1):74-80
[30]Furudoi A, Tanaka S, Haruma K, et al.Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma.Oncology,2002,62(2):157-66.
[31]Xie XD, Qu SX, Zheng ZD, et al.Relation of lymphatic microvessel density detected by monoclonal antibody D2-40 with VEGF-C expression in breast cancer. Zhonghua ZhongLiu Za Zhi,2008,30(5):356-60.
[32]Tsutsumi S, Kuwao H, Snimura T, et al.Vascular endothelial growth factor-C (VEGF-C) expression in PT2 gastric cancer. Hepatogastroenterology,2005,52:629-32.
[33]Liu P, Chen W, Zhu H, Liu B, et al. Expression of VEGF-C correlates with a poor prognosis based on analysis of prognostic factors in 73 patients with esophageal squamous cell carcinomas.Jpn J Clin Oncol.2009,39(10):644-50.
[34]Kitadai Y, Amioka T, Haruma K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Int J Cancer,2001,93 (5):662-6.
[35]Byeon J S, J ung HY, Lee YJ, et al. Clinicopathological significance of vascular endothelial growth factor-C and cyclooxygenase-2 in esophageal squamous cell carcinoma.Gastroenterol Hepatol,2004,19 (6):648-54.
[36]Noguchi T, Takeno S, Shibata T, et al. VEGF-C expression correlates with histolo-gical differentiation and metastasis in squamous cell car-cinoma of the esophagus. Oncol Rep,2002,9 (5):995-9.
[37]Pan XF, Bao GL, Fang WT, et al. VEGF-C mRNA expression and its relationship with clinicopathological parameters in ESCC. Clin J Oncol,2008,30(6):437-40.
[38]Do S, Araujo ES, Kalil RK, et al. Expression of embryonic lethal abnormal vision (ELAV)-like protein HuR and cyclooxygenase-2(COX-2) in Ewing sarcoma. Tumori, 2008,94:347-50.
[39]Niesporek S, Kristiansen G, Thoma A, et al. Expression of the ELAV-like protein HuR in human prostate carcinoma is an indicator of disease relapse and linked to COX-2 expression. International Journal of Oncology,2008,32:341-7.
[40]Yoo PS, Mulkeen AL, Cha CH. Posttranscrip tional regulation of vascular endothelial growth factor:imp lications for tumor angiogenesis. World J Gastroenterol,2006,12 (31):4937-42.
[41]Sengup ta S, Jang BC, W u M T, et al. The RNA-binding protein HuR regulates the expression of cyclooxygenase-2. J Biol Chem,2003,278 (27):25227-33.
[42]Lim SJ, Kim H I, Kim JY, et al. Expression of HuR is associated with increased cyclooxygenase-2 expression in uterine cervical carcinoma. Int J Gynecol Pathol, 2007,26 (3):229-34.
[43]Tamura M, Ohta Y.Serum vascular endothelial growth factor-C level in patients with primary monsmall cell lung carcinoma.A possible diagnostic tool for lymph node metastasis.Cancer,2003,98:1217-22.
[44]Tamura M, Oda M, Matsumoto I, et al.The combination assay with circulating vascular endothelial growth factor (VEGF)-C, matrix metalloprote-inase-9, and VEGF for diagnosing lymph node metastasis in patients with non-small cell lung cancer. Ann Surg Oncol.2004, 11(10):928-33.
[45]Mitsuhashi A, Suzuka K, Yamazawa K,Cancer, etal,Serum vascular endothelial growth factor (VEGF) and VEGF-C levels as tumor markers in patients with cervical carcinoma.2005,103(4):724-30.
[46]Mathur SP, Mathur RS, Gray EA, etal. Serum vascular endothelial growth factor C (VEGF-C) as a specific biomarker for advanced cervical cancer:Relationship to insulin-like growth factor II (IGF-Ⅱ), IGF binding protein 3 (IGF-BP3) and VEGF-A [corrected] Gynecol Oncol.2005 Sep; 98(3):467-83
[47]Alabi AA, Suppiah A, Madden LA, et al. Preoperative serum levels of serum VEGF-C is associated with distant metastasis in colorectal cancer patients. Int J Colorectal Dis. 2009,24(3):269-74.
[48]Xu T, Chen D. Serum vascular endothelial growth factor-C and vascular endothelial growth factor level in patients with colorectal carcinoma and clinical significance. Journal of HuazhongUniversity of Science and Technology,2006,26:329-331
[49]Krzystek-Korpacka M, Matusiewicz M, Diakowska D, etal. Up-regulation of VEGF-C secreted by cancer cells and not VEGF-A correlates with clinical evaluation of lymph node metastasis in esophageal squamous cell carcinoma (ESCC). Cancer Lett,2007, 249(2):171-7.
[50]Kozlowski M, Kowalczuk O, Milewski R, et al.Serum vascular endothelial growth factors C and D in patients with oesophageal cancer.Eur J Cardiothorac Surg.2010, Mar 10.
[51]Giessen K, Di-Marco S, Clair E, et al. RNA-mediated HuR depletion leads to the inhibition of muscle cell differentiation.J Biol Chem,2003,47:47119-28.
[52]李勇,杨进强,赵增仁等.’VEGF-C反义寡核苷酸抑制人胃癌裸鼠移植瘤淋巴管生成的实验研究[J].中国肿瘤临床,2007,34(8)：437-40。
[1]Su JL, Yang PC, Shih JY,et al.The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells.Cancer Cell,2006,9(3):209-23.
[2]Takizawa H, Kondo K, Fujino H, et al. The balance of VEGF-C and VEGFR-3 mRNA is a predictor of lymph node metastasis in non-small cell lung cancer. Br J Cancer, 2006,95(1):75-79.
[3]Staker SA, Achen MG, Jussila L, et al. Lymphangiogenesis and Cancer Metastasis. Nat Rev Cancer,2002,2 (8):573-78.
[4]Wang JG, Collinge M, Ramgolam V, et al.LFA 1 dependent HuR nuclear export and cytokine mRNA stabilization in T cell activation. J Immunol,2006,76 (4):2105.
[5]Wang W, Caldwell MC, Lin S, et al. HuR regulates cyclinA and cyclinBl mRNA stability during cell proliferation.E MBO J,2000,19(10):2340.
[6]Ulus A, Stephanie L, Curry I,et al. Regulation of Eotaxin Gene expression by TNF-a and IL-4 through mRNA stabilization:, involvement of the RNA-binding proteinHuR.J Immunol,2003,171 (10):4369-78.
[7]Levy N, Chung S, Furneaux H, et al. Hypoxic stabilization of vascular endothelial growth factor mRNA by the RNA-binding protein HuR. Biol Chem,1998,273(11): 6417-23.
[8]Sengup ta S, JangBC, WuMT, et al. The RNA-binding protein HuR regulates the expr-ession of cyclooxygenase-2. J Biol Chem,2003,278 (27):25227-33.
[9]Wang J, Zhao Wp, Guo Y,et al. The Expression of RNA-Binding Protein HuR in Non-Small Cell Lung Cancer Correlates with Vascular Endothelial Growth Factor-C Expression and Lymph Node Metastasis. Oncology,2009,76:420-29.
[10]Su JL, Shih JY, YenML, et al. Cyclooxygenase-2 induces EP1-and HER-2/Neu-dependent vascular endothelial growth factor-C upregulation:a novelmechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res,2004,64 (2):554-64.
[11]Timoshenko AV, Chakraborty C, Wagner GF, et al. COX-2 mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. Br J Cancer,2006,94 (8):1154-63.
[12]Katsuta M, Miyashita M, Makinoa H, et al. Correlation of hypoxia inducible factor-la with lymphatic metastasis via vascular endothelial growth factor-C in human esophageal cancer. Exp Mol Pathol,2005,78 (2):123-30.
[13]Chang LK, Garcia CG, Farnebo F, et al. Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA,2004,101 (32):11658-63.
[14]Cao R, BjorndahlMA, Religa P, et al. PDGF-BB induces intratumoral lymphangio-genesis and promotes lymphatic metastasis. Cancer Cell,2004,6 (4):333-45.
[15]Morisada T,Oike Y,Yamada Y,et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood,2005,105 (12):4649-56.
[16]RistimakiA,Narko K,Enholm B,et al. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endo-thelial growth factor-C. J Biol Chem,1998,273 (14):8413-18.
[17]Subhojit Roy, Albert Chu, John Q, et al. D2-40 a novel monoclonal antibody against theM2A antigen as a marker to distinguish hemangiobla-stomas from renal cell carcinomas. Acta Neuropathol (Berl),2005,109 (5):497-502.
[18]Fukunaga M. Expression of D2-40 in lymphatic endothelium of normaltissues and in vascular tumours. Histopathology,2005,46(4):396-402.
[19]Saad RS, Lindner JL, Liu Y, et al. Lymphatic vessel density as prognostic marker in esophageal adenocarcinoma. Am J Clin Pathol,2009,131(1):92-8.
[20]Kitadai Y, Amioka T, Haruma K, et al. Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Int J Cancer,2001,93 (5):662-66.
[21]Byeon JS, J ung HY, Lee YJ, et al. Clinicopathological significance of vascular endothelial growth factor-C and cyclooxygenase-2 in esophageal squamous cell carcinoma.Gastroenterol Hepatol,2004,19 (6):648-54.
[22]Tzao Ching, Lee SC, Tung HJ, et al. Expression of hypoxia-inducible factor (HIF)-la and vascular endothelial growth factor (VEGF)-D as outcome predictors in resected esophageal squamous cell carcinoma.Disease Markers,2008, (25) 141-48.
[23]Noguchi T,Takeno S,Shibata T,et al.VEGF-C expression correlates with histological differentiation and metastasis in squamous cell carcinoma of the esophagus. Oncol Rep,2002,9 (5):995-99.
[24]Pan XF, Bao GL, Fang WT,et al.VEGF-C mRNA expression and its relationship with clinicopathological parameters in ESCC. Clin J Oncol,2008,30(6):437-40.
[25]刘巍,郝希山,陈勇等.1526例胸段食管癌及贲门癌淋巴结转移状况分析[J].中国肿瘤临床,2008,35(1)：601-05.
[26]Mrena J, Wiksten J, Thiel A, et al. Cyclooxygenase-2 Is an Independent Prognostic Factor in Gastric Cancer and Its Expression Is Regulated by the Messenger RNA Stability Factor HuR. Clin Cancer Res,2005,11(20):7362-68.