HuR与COX-2在上皮性卵巢癌表达与预后因素的相关性研究
摘要
目的:检测HuR和COX-2在卵巢上皮性癌中的表达,研究HuR与COX-2二者的相关性,结合临床病理资料及随访资料,探讨HuR和COX-2与卵巢上皮性癌临床病理参数、预后风险的关系,寻求卵巢癌发生发展的可能途径和预后因素。
方法
1收集原发卵巢上皮性癌组织68例,交界性卵巢肿瘤10例,正常卵巢组织5例行免疫组织化学染色SP法检测HuR与COX-2的表达。
2应用RT-PCR方法检测正常卵巢上皮组织和卵巢上皮性癌(浆液性、黏液性及子宫内膜样)组织HuR mRNA的表达情况。
3随访每例卵巢癌患者的预后,并进行Kaplan-Meier生存分析,及运用Cox比例风险模型进行生存率的多因素分析,评价预后生存指标。
结果
1 HuR在卵巢肿瘤组织胞核中的表达
HuR在卵巢上皮性癌胞核中阳性表达率为76.47%(52/68)明显高于交界性卵巢肿瘤胞核的阳性表达率30.00%(3/10)和正常卵巢组织(正常卵巢组织无表达)(P<0.05);HuR在交界性卵巢肿瘤的表达与正常卵巢组织比较无显著性差异(P>0.05)。
2 HuR在卵巢上皮性肿瘤组织胞质中的表达
HuR在卵巢上皮性癌和交界性卵巢肿瘤胞质中的阳性表达率分别为45.60%(31/68)、10.00%(1/10),正常卵巢组织无表达;胞质HuR在恶性卵巢肿瘤组织的表达与交界性卵巢肿瘤和正常卵巢组织比较差异有显著性(P<0.05);胞质HuR在交界性卵巢肿瘤的表达与正常卵巢组织比较无显著性差异(P>0.05)。
3胞质HuR的表达与卵巢上皮性癌临床病理因素的关系
胞质HuR的表达与卵巢上皮性癌组织学类型、淋巴结转移和年龄无关,与组织学分级和临床期别有关。组织分化高的卵巢上皮性癌胞质HuR的表达较中-低分化组的表达弱,差异有显著性(P<0.05)。胞质HuR的表达在中分化与低分化之间无显著性差异(P>0.05);临床分期中Ⅲ～Ⅳ期胞质HuR的表达显著高于Ⅰ～Ⅱ期,差异有显著性(P<0.05)。
4 COX-2在卵巢上皮性肿瘤组织中的表达
COX-2在卵巢上皮性癌、交界性卵巢肿瘤及正常卵巢组织中表达的阳性率依次为:67.64%(46/68)、60.00%(6/10)、0.00%(0/5)。COX-2在卵巢上皮性癌和交界性卵巢肿瘤的表达与正常卵巢组织比较差异有显著性(P<0.05);而在卵巢上皮性癌的表达与交界性卵巢肿瘤比较无显著性差异(P>0.05)。
5 COX-2的表达与卵巢上皮性癌临床病理因素的关系
COX-2的表达与卵巢上皮性癌临床分期和淋巴结转移有关,与组织学类型、组织学分级和年龄无关。COX-2在临床分期Ⅲ～Ⅳ期的表达率显著高于Ⅰ～Ⅱ期,差异有显著性(P<0.05);有淋巴结转移者COX-2的表达高于无淋巴结转移者,差异有显著性(P<0.05)。
6 HuR与COX-2表达相关性分析
在卵巢上皮性癌中胞质HuR的表达与COX-2的表达增高呈正相关(P<0.05)。
7生存分析
Kaplan-Meier生存分析提示:卵巢上皮性癌组胞质HuR的表达增加、COX-2的高表达与患者无进展生存期(progression-free survival )和总生存期(overall survival)有关。Cox比例风险模型提示:胞质HuR的表达是独立的预后指标,其他预后指标是临床分期与第一次手术残余瘤大小。
[结论]
1 HuR与COX-2在卵巢上皮性癌的表达明显增高,胞质HuR的表达与COX-2的表达呈正相关,提示胞质HuR与COX-2的过表达可能与卵巢癌的发生发展密切相关。
2胞质HuR的表达增高对生存率及预后有影响,可作为预后指标。
Objective :The aim of this study was to check the expressions of HuR and COX-2 in epithelial ovarian cancer, and examine the relativity between HuR and COX-2.With various clinicopathologic characteristics we investigated the influence of HuR and COX-2 expression on the prognosis and parameter of clinical and pathological and attempt to seek the pathway to prevent the occurrence and development of epithelial ovarian cancer .
Methods 1 S-P immunohistochemical technique was used to
examine the expression of HuR and COX-2 in 68 epithelial ovarian carcinoma,10 borderline tumors of the ovary and 5 normal ovary tissues.
2 We applied RT-PCR check and measure the expressions of HuR and COX-2 in normal ovarian epithelial tissue and ovarian epithelial cancer tissues .
3 The relation of HuR and COX-2 expression with clinical pathological parameter was estimated by correlation analysis.Kaplan-Meier and Cox proportional regression survival analyses were used to compare normal and abnormal expression of HuR and COX-2.
Results
1 Expression of nuclear HuR in ovarian carcinoma . The nuclear expression of HuR in epithelial ovarian cancer tissue(76.47%)was remarkably higher than that in borderline epithelial ovarian tumor tissues(30.00%)and normal ovarian tissues(0%),and had no remarkably differences between the borderline epithelial ovarian tumor and normal ovarian tissue. (P>0.05)
2 Expression of cytoplasmic HuR in ovarian carcinoma .
The positive expression rates of cytoplasmic HuR in maglinant、borderline epithelial ovarian tumors and normal ovarian tissues were 45.60%、10%、0% respectively.
The cytoplasmic expression of HuR in epithelial ovarian cancer was a significantly higher than that in borderline tumors and normal ovarian tissues and had no remarkably differences between the borderline tumors and normal ovarian tissues .
3 Statistical analyses showed that the positive expression rate of cytoplasmic HuR in epithelial ovarian carcinoma was closely correlated with histological grade, and FIGO stage,but not correlated with histological type, lymphnode metastasis and the age of the patients.The rates of expression of cytoplasmic HuR in G2 and G3 groups were higher than that in G1 group (P<0.05), in stagesⅢandⅣwere higher than that in stagesⅠandⅡ(P<0.05).
4 The positive expression rates of COX-2 in malignant ovarian cancer、borderline ovarian tumor and normal ovarian tissues were 67.64%、60.00%、0.00%, respectively .There was a higher difference between malignant、borderline ovarian cancer and normal ovarian tissues,but no remarkably differences between malignant and borderline ovarian tumors .
5 COX-2 immunostaining and clinicpathological parameters : statistical analyses showed that the positive expression rate of COX-2 in epithelial ovarian carcinoma was closely correlated with FIGO stage and lymphnode metastasis ,but not correlated with histological type, histological grade and the age of the patients. The rates of expression of COX-2 in stagesⅢandⅣwere higher than that in stagesⅠandⅡ(P<0.05).The cases having lymphnode metastasis had higher COX-2 expression than those having no lymphnode metastasis (P<0.05).
6 Correlation between cytoplasmic HuR immunostaining and COX-2 expression : statistical analyses showed a significant correlation between cytoplasmic HuR and COX-2 expressions in epithelial ovarian carcinoma .
7 Survival analysis Kaplan-Merier showed that an increased cytoplasmic expression of HuR was a negative prognostic factors for progression-free survival as well as for overall survival(P<0.05).Multivariate Cox regression analysis showed:cytoplasmic expression of HuR was an independent prognostic parameter for reduced overall survival.Other independent parameter were FIGO stage as well as intraoperative residual tumor .
Conclusion
1 The expression of HuR and COX-2 were higher in the epithelial ovarian carcinoma and the cytoplasmic expression of HuR was significantly correlated with the expression of COX-2. These results suggest that increased cytoplasmic expression of HuR and COX-2 expression may play important roles in the growth and development of epithelial ovarian carcinoma.
2 The increased cytoplasmic expression of HuR was associated with survival and prognosis and may be act as a prognostic factor in ovarian carcinoma .
方法
1收集原发卵巢上皮性癌组织68例,交界性卵巢肿瘤10例,正常卵巢组织5例行免疫组织化学染色SP法检测HuR与COX-2的表达。
2应用RT-PCR方法检测正常卵巢上皮组织和卵巢上皮性癌(浆液性、黏液性及子宫内膜样)组织HuR mRNA的表达情况。
3随访每例卵巢癌患者的预后,并进行Kaplan-Meier生存分析,及运用Cox比例风险模型进行生存率的多因素分析,评价预后生存指标。
结果
1 HuR在卵巢肿瘤组织胞核中的表达
HuR在卵巢上皮性癌胞核中阳性表达率为76.47%(52/68)明显高于交界性卵巢肿瘤胞核的阳性表达率30.00%(3/10)和正常卵巢组织(正常卵巢组织无表达)(P<0.05);HuR在交界性卵巢肿瘤的表达与正常卵巢组织比较无显著性差异(P>0.05)。
2 HuR在卵巢上皮性肿瘤组织胞质中的表达
HuR在卵巢上皮性癌和交界性卵巢肿瘤胞质中的阳性表达率分别为45.60%(31/68)、10.00%(1/10),正常卵巢组织无表达;胞质HuR在恶性卵巢肿瘤组织的表达与交界性卵巢肿瘤和正常卵巢组织比较差异有显著性(P<0.05);胞质HuR在交界性卵巢肿瘤的表达与正常卵巢组织比较无显著性差异(P>0.05)。
3胞质HuR的表达与卵巢上皮性癌临床病理因素的关系
胞质HuR的表达与卵巢上皮性癌组织学类型、淋巴结转移和年龄无关,与组织学分级和临床期别有关。组织分化高的卵巢上皮性癌胞质HuR的表达较中-低分化组的表达弱,差异有显著性(P<0.05)。胞质HuR的表达在中分化与低分化之间无显著性差异(P>0.05);临床分期中Ⅲ～Ⅳ期胞质HuR的表达显著高于Ⅰ～Ⅱ期,差异有显著性(P<0.05)。
4 COX-2在卵巢上皮性肿瘤组织中的表达
COX-2在卵巢上皮性癌、交界性卵巢肿瘤及正常卵巢组织中表达的阳性率依次为:67.64%(46/68)、60.00%(6/10)、0.00%(0/5)。COX-2在卵巢上皮性癌和交界性卵巢肿瘤的表达与正常卵巢组织比较差异有显著性(P<0.05);而在卵巢上皮性癌的表达与交界性卵巢肿瘤比较无显著性差异(P>0.05)。
5 COX-2的表达与卵巢上皮性癌临床病理因素的关系
COX-2的表达与卵巢上皮性癌临床分期和淋巴结转移有关,与组织学类型、组织学分级和年龄无关。COX-2在临床分期Ⅲ～Ⅳ期的表达率显著高于Ⅰ～Ⅱ期,差异有显著性(P<0.05);有淋巴结转移者COX-2的表达高于无淋巴结转移者,差异有显著性(P<0.05)。
6 HuR与COX-2表达相关性分析
在卵巢上皮性癌中胞质HuR的表达与COX-2的表达增高呈正相关(P<0.05)。
7生存分析
Kaplan-Meier生存分析提示:卵巢上皮性癌组胞质HuR的表达增加、COX-2的高表达与患者无进展生存期(progression-free survival )和总生存期(overall survival)有关。Cox比例风险模型提示:胞质HuR的表达是独立的预后指标,其他预后指标是临床分期与第一次手术残余瘤大小。
[结论]
1 HuR与COX-2在卵巢上皮性癌的表达明显增高,胞质HuR的表达与COX-2的表达呈正相关,提示胞质HuR与COX-2的过表达可能与卵巢癌的发生发展密切相关。
2胞质HuR的表达增高对生存率及预后有影响,可作为预后指标。
Objective :The aim of this study was to check the expressions of HuR and COX-2 in epithelial ovarian cancer, and examine the relativity between HuR and COX-2.With various clinicopathologic characteristics we investigated the influence of HuR and COX-2 expression on the prognosis and parameter of clinical and pathological and attempt to seek the pathway to prevent the occurrence and development of epithelial ovarian cancer .
Methods 1 S-P immunohistochemical technique was used to
examine the expression of HuR and COX-2 in 68 epithelial ovarian carcinoma,10 borderline tumors of the ovary and 5 normal ovary tissues.
2 We applied RT-PCR check and measure the expressions of HuR and COX-2 in normal ovarian epithelial tissue and ovarian epithelial cancer tissues .
3 The relation of HuR and COX-2 expression with clinical pathological parameter was estimated by correlation analysis.Kaplan-Meier and Cox proportional regression survival analyses were used to compare normal and abnormal expression of HuR and COX-2.
Results
1 Expression of nuclear HuR in ovarian carcinoma . The nuclear expression of HuR in epithelial ovarian cancer tissue(76.47%)was remarkably higher than that in borderline epithelial ovarian tumor tissues(30.00%)and normal ovarian tissues(0%),and had no remarkably differences between the borderline epithelial ovarian tumor and normal ovarian tissue. (P>0.05)
2 Expression of cytoplasmic HuR in ovarian carcinoma .
The positive expression rates of cytoplasmic HuR in maglinant、borderline epithelial ovarian tumors and normal ovarian tissues were 45.60%、10%、0% respectively.
The cytoplasmic expression of HuR in epithelial ovarian cancer was a significantly higher than that in borderline tumors and normal ovarian tissues and had no remarkably differences between the borderline tumors and normal ovarian tissues .
3 Statistical analyses showed that the positive expression rate of cytoplasmic HuR in epithelial ovarian carcinoma was closely correlated with histological grade, and FIGO stage,but not correlated with histological type, lymphnode metastasis and the age of the patients.The rates of expression of cytoplasmic HuR in G2 and G3 groups were higher than that in G1 group (P<0.05), in stagesⅢandⅣwere higher than that in stagesⅠandⅡ(P<0.05).
4 The positive expression rates of COX-2 in malignant ovarian cancer、borderline ovarian tumor and normal ovarian tissues were 67.64%、60.00%、0.00%, respectively .There was a higher difference between malignant、borderline ovarian cancer and normal ovarian tissues,but no remarkably differences between malignant and borderline ovarian tumors .
5 COX-2 immunostaining and clinicpathological parameters : statistical analyses showed that the positive expression rate of COX-2 in epithelial ovarian carcinoma was closely correlated with FIGO stage and lymphnode metastasis ,but not correlated with histological type, histological grade and the age of the patients. The rates of expression of COX-2 in stagesⅢandⅣwere higher than that in stagesⅠandⅡ(P<0.05).The cases having lymphnode metastasis had higher COX-2 expression than those having no lymphnode metastasis (P<0.05).
6 Correlation between cytoplasmic HuR immunostaining and COX-2 expression : statistical analyses showed a significant correlation between cytoplasmic HuR and COX-2 expressions in epithelial ovarian carcinoma .
7 Survival analysis Kaplan-Merier showed that an increased cytoplasmic expression of HuR was a negative prognostic factors for progression-free survival as well as for overall survival(P<0.05).Multivariate Cox regression analysis showed:cytoplasmic expression of HuR was an independent prognostic parameter for reduced overall survival.Other independent parameter were FIGO stage as well as intraoperative residual tumor .
Conclusion
1 The expression of HuR and COX-2 were higher in the epithelial ovarian carcinoma and the cytoplasmic expression of HuR was significantly correlated with the expression of COX-2. These results suggest that increased cytoplasmic expression of HuR and COX-2 expression may play important roles in the growth and development of epithelial ovarian carcinoma.
2 The increased cytoplasmic expression of HuR was associated with survival and prognosis and may be act as a prognostic factor in ovarian carcinoma .
引文
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6 Cok S.J,Acton S.J,Morrison A.R.The proximal region of the 3’-untranslated region of Cyclooxygenase-2 is recognized by a multimeric protein complex containing HuR,TIA-1,TIARsandehnRNP.J.Biol.Chem,2003,278(12):36157-36162.
7 J.Mrena,J.-P.Wiksten,A.Thiel,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):7362-7368.
8 Niesporek,G.Kristiansen,H.Guski,et al.Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expressionin in human breast carcinoma.Clin.Cancer Res,2004,10(16):5580-5586.
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101M.Heinonen,P.Bono,K.Narko,et al.Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma.Caner Res, 2005,65(6):2157-2161.
11 Lopez de Silanes I, Fan J,Yang X, et al. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene ,2003,22:7146-7154.
12 Nabors L.B,Gillespie G.Y,Harkins L,et al.HuR, a RNA factor, is expressed in malignant brain tumors and binds to adenine-and uridine-rich elements within the 3' untranslated regions of cytokine and angiogenic factor mR-NAs.Cancer Res,2001,61:2154-2161.
13 Kau T.R,Silver P.A.Nuclear transport as a target for cell growth.Drug Disc.Today,2003,16(8):78-85.
14 Denket C,Koch I,Von keyserling K N. Expression of the ELAV-like protein HuR in human colon cancer:association with tumor stage and cyclooxygenase-2.Mod Pathol, 2006,19(4):564-572.
15 Erkinheimo TL,Lassus H,Sivula A,et al.Cytoplasmic HuR expression correlates with poor outcome and with cyclooxygenase-2 expression in serous ovarian carcinoma .Cancer Res, 2003,63:7591-4
16 Denkert C, Weichert W, Pest S,et al. Overexpression of the embryonic-lethal abnormal vision-like protein HuR ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase-2 expression.Cancer Res, 2004,64:189-95.
17 Mills GB,Bast RC Jr ,Srivastava S.Future for ovarian cancer screening:novel markers from emerging technologies of transcripional profiling and proteomics. J Natl Cancer Inst,2001,93:1458-1464.
18 Denkert C,Kobel M,Pest S,et al.Expression of cyclooxygenase-2 is an independent prognostic factor in human ovarian carcinoma. Am J Pathol,2002,160(3):893-903.
19 Sureban SM,Murmu N,Rodriguez P.Functional antagonism beween RNA binding proteins HuR and CUGBPZ determines the fate of cox-2 mRNA translation. Gastroenterology, 2007,132(3):1055-1065.
20 L.B.Nabors,E .Suswam,Y.Huang,et al.Tumor Necrosis Factor﹛alpha﹜ Induces Angiogeic Factor Up-Regulation in Malignant Glioma Cells:A Role for RNA Stabilization and HuR.Cancer Res,2003,63(14):4181-4187.
21 Grau SJ,Trillsch F,Herms J;et al.Expression of VEGFR3 in glioma endothelium correlates with tumor grade.J Neuro Oncol,2007,82(2):141-150.
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1 Mazan M,Gallan S ,Lopez de SI,et al.RNA-binding protein HuR enhances P53 translation in response to ultraviolet light irradiation.Proc Natl cad Sci U S A,2003,100(14):8354-8359.
2 K.Leandersson,K.Riesbeck,and T.Andersson.Wnt-5a mRNA translation is suppressed by the Elav-like protein HuR in human breastqepithelialwcells.Nucleic Acids Res,2006,34 (14):3988-3999.
3 Landen CN Jr,Mathur SP ,Richardson MS,et al.Expression of cyclooxygenase-2 in cervical,endometrial,and ovarian malignancies.Am J Obstet Gynecol,2003,188(5):1174-1176.
4 Li S,Miner K,Fannin R,et al. Cyclooxygenase-1 and 2 in normal and malignant human ovarian epithelium.Gynecol Oncol,2004,92(2):622-627.
5 Sengupta S, Jang BC, Wu MT, et al. The RNA-binding protein HuR regulates the expression of cyclooxygenase-2. J Biol.Chem, 2003,278:25227-33.
6 Cok S.J,Acton S.J,Morrison A.R.The proximal region of the 3’-untranslated region of Cyclooxygenase-2 is recognized by a multimeric protein complex containing HuR,TIA-1,TIARsandehnRNP.J.Biol.Chem,2003,278(12):36157-36162.
7 J.Mrena,J.-P.Wiksten,A.Thiel,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):7362-7368.
8 Niesporek,G.Kristiansen,H.Guski,et al.Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expressionin in human breast carcinoma.Clin.Cancer Res,2004,10(16):5580-5586.
9 Jin SH, Kim TI, Yang KM, et al. Thalidomide destabilizes cyclooxygenase-2 mRNA by inhibiting p38 mitogen-activated protein kinase and cytoplasmic shuttling of HuR. Eur J Pharmacol, 2007,558(1-3):14-20.
101M.Heinonen,P.Bono,K.Narko,et al.Cytoplasmic HuR expression is a prognostic factor in invasive ductal breast carcinoma.Caner Res, 2005,65(6):2157-2161.
11 Lopez de Silanes I, Fan J,Yang X, et al. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene ,2003,22:7146-7154.
12 Nabors L.B,Gillespie G.Y,Harkins L,et al.HuR, a RNA factor, is expressed in malignant brain tumors and binds to adenine-and uridine-rich elements within the 3' untranslated regions of cytokine and angiogenic factor mR-NAs.Cancer Res,2001,61:2154-2161.
13 Kau T.R,Silver P.A.Nuclear transport as a target for cell growth.Drug Disc.Today,2003,16(8):78-85.
14 Denket C,Koch I,Von keyserling K N. Expression of the ELAV-like protein HuR in human colon cancer:association with tumor stage and cyclooxygenase-2.Mod Pathol, 2006,19(4):564-572.
15 Erkinheimo TL,Lassus H,Sivula A,et al.Cytoplasmic HuR expression correlates with poor outcome and with cyclooxygenase-2 expression in serous ovarian carcinoma .Cancer Res, 2003,63:7591-4
16 Denkert C, Weichert W, Pest S,et al. Overexpression of the embryonic-lethal abnormal vision-like protein HuR ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase-2 expression.Cancer Res, 2004,64:189-95.
17 Mills GB,Bast RC Jr ,Srivastava S.Future for ovarian cancer screening:novel markers from emerging technologies of transcripional profiling and proteomics. J Natl Cancer Inst,2001,93:1458-1464.
18 Denkert C,Kobel M,Pest S,et al.Expression of cyclooxygenase-2 is an independent prognostic factor in human ovarian carcinoma. Am J Pathol,2002,160(3):893-903.
19 Sureban SM,Murmu N,Rodriguez P.Functional antagonism beween RNA binding proteins HuR and CUGBPZ determines the fate of cox-2 mRNA translation. Gastroenterology, 2007,132(3):1055-1065.
20 L.B.Nabors,E .Suswam,Y.Huang,et al.Tumor Necrosis Factor﹛alpha﹜ Induces Angiogeic Factor Up-Regulation in Malignant Glioma Cells:A Role for RNA Stabilization and HuR.Cancer Res,2003,63(14):4181-4187.
21 Grau SJ,Trillsch F,Herms J;et al.Expression of VEGFR3 in glioma endothelium correlates with tumor grade.J Neuro Oncol,2007,82(2):141-150.