卵巢癌c-Fos的表达及其与MAPK信号通路关系的研究
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摘要
目的:研究c-Fos蛋白在人卵巢癌细胞和组织中的表达及其与丝裂原活化蛋白激酶(mitogen activated protein kinases, MAPKs)信号通路关系的研究。
方法:采用MaxVisionTM免疫组织化学法研究c-Fos蛋白和磷酸化细胞外调节激酶1/2(phosphated extracellular-signal regulated kinase 1/2, p-ERK1/2)蛋白在正常卵巢组织、卵巢良性肿瘤组织、上皮性卵巢癌组织中的表达,用MTT比色法检测PD98059对卵巢癌细胞株HO-8910活性的影响,用流式细胞仪检测PD98059对HO-8910细胞周期的变化,用MaxVisionTM免疫细胞化学法研究c-Fos蛋白的表达,用western blot检测细胞内c-Fos蛋白及p-ERK1/2蛋白的表达。
结果:c-Fos蛋白及p-ERK1/2蛋白在上皮性卵巢癌组织中过度表达,与正常卵巢组织、卵巢良性肿瘤组织相比差异十分显著,并且c-Fos蛋白和p-ERK1/2蛋白的表达量与分化程度呈负相关(rs= -0.445, P<0.01; rs=-0.389, P <0.05 respectively),与临床分期呈正相关( rs=0.492, P<0.01; rs=0.521, P <0.01 respectively),与淋巴结转移呈正相关(rs=0.338, P <0.05; rs=0.343, P <0.05 respectively),与年龄、组织学类型等无关。并且卵巢癌中c-Fos蛋白表达与p-ERK1/2蛋白表达呈正相关(rs=0.409, P<0.01)。与对照组相比,150μmol/L和200μmol/L PD98059组可显著降低人卵巢癌细胞株HO-8910的活性(P<0.01);PD98059呈浓度依赖性抑制细胞p-ERK1/2蛋白的表达及抑制细胞进入S期(P<0.01);PD98059还能抑制细胞内c-Fos蛋白的表达。
结论:ERK1/2信号通路可能通过c-Fos蛋白而促进卵巢癌的发生。
Objective: To study the expression of c-Fos in the human ovarian carcinoma tissues and cell line HO-8910 and the role of c-Fos in the mitogen activated protein kinases(MAPKs) signal transduction in the human ovarian carcinoma.
Methods: The MaxVisionTM immunohischemistry was used to observe the expression of c-Fos and phosphated extracellular-signal regulated kinase 1/2(p-ERK1/2) in the normal ovary tissues, benign ovary tissues and epithelial ovarian carcinoma. The MTT was used to observe the effect of PD98059 on the viability of human ovarian carcinoma cell line HO-8910 and the flow cytometry was utilized to observe the cell cycle. The MaxVisionTM immunocytochemistry was used to observe the expression of c-Fos in the human ovarian carcinoma cell line HO-8910. The western blot was used to observe the content of p-ERK1/2 and c-Fos in the human ovarian carcinoma cell line HO-8910.
Results: Compared with the normal ovary tissues and benign ovary tissues, the contents of c-Fos and p-ERK1/2 in the epithelial ovarian carcinoma increased significantly. We also inverstigated that the expression of c-Fos and p-ERK1/2 in ovarian carcinoma were correlated with differentiation negatively (rs=-0.445, P =0.004; rs=-0.389, P <0.05 respectively), with clinical staging positively (rs=0.492, P=0.001; rs=0.521, P <0.01 respectively), with lymphatic metastasis positively (rs=0.338, P=0.033; rs=0.343, P <0.05 respectively) and had no correlation with age and histological types. The expression of c-Fos in ovarian carcinoma was correlated with p-ERK1/2 positively (rs=0.409, P<0.01). Compared with the control group, PD98059 with 150μmol/L and 200μmol/L concentration could significantly inhibit the viability of the ovarian carcinoma cell line HO-8910 (P<0.01); PD98059 could inhibit the content of p-ERK1/2 and S-phase entry of the ovarian carcinoma cell in a dose-dependent manner (P<0.01); PD98059 could also inhibit the expression of c-Fos in the cells.
Conclusion: ERK1/2 might play an important role in the initiation and development of the ovarian carcinoma through c-Fos.
方法:采用MaxVisionTM免疫组织化学法研究c-Fos蛋白和磷酸化细胞外调节激酶1/2(phosphated extracellular-signal regulated kinase 1/2, p-ERK1/2)蛋白在正常卵巢组织、卵巢良性肿瘤组织、上皮性卵巢癌组织中的表达,用MTT比色法检测PD98059对卵巢癌细胞株HO-8910活性的影响,用流式细胞仪检测PD98059对HO-8910细胞周期的变化,用MaxVisionTM免疫细胞化学法研究c-Fos蛋白的表达,用western blot检测细胞内c-Fos蛋白及p-ERK1/2蛋白的表达。
结果:c-Fos蛋白及p-ERK1/2蛋白在上皮性卵巢癌组织中过度表达,与正常卵巢组织、卵巢良性肿瘤组织相比差异十分显著,并且c-Fos蛋白和p-ERK1/2蛋白的表达量与分化程度呈负相关(rs= -0.445, P<0.01; rs=-0.389, P <0.05 respectively),与临床分期呈正相关( rs=0.492, P<0.01; rs=0.521, P <0.01 respectively),与淋巴结转移呈正相关(rs=0.338, P <0.05; rs=0.343, P <0.05 respectively),与年龄、组织学类型等无关。并且卵巢癌中c-Fos蛋白表达与p-ERK1/2蛋白表达呈正相关(rs=0.409, P<0.01)。与对照组相比,150μmol/L和200μmol/L PD98059组可显著降低人卵巢癌细胞株HO-8910的活性(P<0.01);PD98059呈浓度依赖性抑制细胞p-ERK1/2蛋白的表达及抑制细胞进入S期(P<0.01);PD98059还能抑制细胞内c-Fos蛋白的表达。
结论:ERK1/2信号通路可能通过c-Fos蛋白而促进卵巢癌的发生。
Objective: To study the expression of c-Fos in the human ovarian carcinoma tissues and cell line HO-8910 and the role of c-Fos in the mitogen activated protein kinases(MAPKs) signal transduction in the human ovarian carcinoma.
Methods: The MaxVisionTM immunohischemistry was used to observe the expression of c-Fos and phosphated extracellular-signal regulated kinase 1/2(p-ERK1/2) in the normal ovary tissues, benign ovary tissues and epithelial ovarian carcinoma. The MTT was used to observe the effect of PD98059 on the viability of human ovarian carcinoma cell line HO-8910 and the flow cytometry was utilized to observe the cell cycle. The MaxVisionTM immunocytochemistry was used to observe the expression of c-Fos in the human ovarian carcinoma cell line HO-8910. The western blot was used to observe the content of p-ERK1/2 and c-Fos in the human ovarian carcinoma cell line HO-8910.
Results: Compared with the normal ovary tissues and benign ovary tissues, the contents of c-Fos and p-ERK1/2 in the epithelial ovarian carcinoma increased significantly. We also inverstigated that the expression of c-Fos and p-ERK1/2 in ovarian carcinoma were correlated with differentiation negatively (rs=-0.445, P =0.004; rs=-0.389, P <0.05 respectively), with clinical staging positively (rs=0.492, P=0.001; rs=0.521, P <0.01 respectively), with lymphatic metastasis positively (rs=0.338, P=0.033; rs=0.343, P <0.05 respectively) and had no correlation with age and histological types. The expression of c-Fos in ovarian carcinoma was correlated with p-ERK1/2 positively (rs=0.409, P<0.01). Compared with the control group, PD98059 with 150μmol/L and 200μmol/L concentration could significantly inhibit the viability of the ovarian carcinoma cell line HO-8910 (P<0.01); PD98059 could inhibit the content of p-ERK1/2 and S-phase entry of the ovarian carcinoma cell in a dose-dependent manner (P<0.01); PD98059 could also inhibit the expression of c-Fos in the cells.
Conclusion: ERK1/2 might play an important role in the initiation and development of the ovarian carcinoma through c-Fos.
引文
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[2] Natarajan M, Saravanan SM, Elson DL. Advanced ovarian carcinoma as a chronic disease: a case report and review[J]. S D J Med, 2003, 56(12):515-521.
[3] Santen RJ, Song RX, McPherson R, et al. The role of mitogen-activated protein (MAP)kinase in breast cancer[J]. J Steroid Biochem Mol Biol, 2002, 80(2):239-256.
[4] Dong C, Davis RJ, Flavell RA. Map kinases in the immune response[ J]. Annu Rev Immunol, 2002, 20: 55-72.
[5] WangY, Kristensen GB, Helland A, et al. Protein Expression and prognostic value of genes in the erb-b signaling pathway in advanced ovarian carcinomas[J]. Am J Clin Patho1, 2005, 124(3): 392-401.
[6] Chang L, Karin M. Mammalian MAP kinase signaling cascades[J]. Nature, 2001, 410(6824): 37- 40.
[7] Hommes DW, Peppelenbosch MP, van Deventer SJ. Mitogen activated protein (MAP) kinase signal transduction pathways and novel anti- inflammatory targets[J]. Gut, 2003, 52(1): 144-151.
[8] Boulton TG, Yancopoulos GD, Gregory JS, et a1. An insulin-stimulated-protein kinase similar to yeast kinases involved in cell cycle control[J]. Science, 1990, 249 (4964): 64- 67.
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