Inhibition of survivin reduces cell proliferation and induces apoptosis in human endometrial cancer
Inhibition of survivin reduces cell proliferation and induces apoptosis in human endometrial cancer
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DOI：
10.1002/cncr.22044
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发表时间：
2006-08-15
期刊：
影响因子：
6.2
通讯作者：
Feng, Youji
中科院分区：
文献类型：
--
作者：
Ai, Zhihong;Yin, Lianhua;Feng, Youji
背景子宫内膜癌是一种常见的妇科恶性肿瘤。子宫内膜癌进展的分子机制尚不清楚，这阻碍了有效治疗的发展。Survivin是新近发现的凋亡抑制因子（inhibitor of apoptosis，Survivin）家族成员，在肿瘤转化过程中调节细胞增殖和凋亡两个关键过程。应用免疫组化、逆转录聚合酶链反应（RT-PCR）和Western blot分析Survivin mRNA和蛋白在正常子宫内膜、不典型子宫内膜和子宫内膜腺癌中的表达水平。为研究Survivin在子宫内膜癌中的生物学功能，采用RNA干扰技术，构建了Survivin小发夹RNA重组质粒，并应用于子宫内膜癌细胞株石川中，以抑制Survivin的表达。此外，还研究了调节survivin表达的信号通路。子宫内膜腺癌中Survivin mRNA和蛋白的表达水平均高于不典型或正常子宫内膜。免疫组化染色显示83.3%（50/60）的子宫内膜腺癌、55.0%（11/20）的不典型子宫内膜和25.0%（5/20）的正常子宫内膜组织中Survivin蛋白阳性。通过RNA干扰抑制survivin可降低石川细胞的增殖并通过下调细胞周期蛋白D1和磷酸化RB以及激活caspase-3和caspase-8诱导细胞凋亡。作者还发现MAPK通路是生存素上游的信号转导通路。表皮生长因子（EGF）和转化生长因子-α（TGF-α）通过激活MAPK途径上调子宫内膜癌细胞中Survivin蛋白的表达。Survivin是子宫内膜癌治疗的一个有吸引力的靶点。生长因子可通过激活MAPK途径调节Survivin的表达。
BACKGROUND. Endometrial cancer is a common gynecologic malignancy among women. The molecular mechanisms involved in the progression of endometrial cancer are unclear, which has hampered the development of an effective treatment. Survivin, a newly identified member of the inhibitor of apoptosis (LAP) family, regulates 2 critical processes in neoplastic transformation: cell proliferation and apoptosis.METHODS. Survivin mRNA and protein expression levels were analyzed in human normal cycling endometrium, atypical endometrium, and endometrial adenocarcinoma by immunohistochemical, reverse-transcriptase polymerase chain reaction (RT-PCR), and Western blot analyses. To study the biological function of survivin in endometrial cancer, RNA interference was applied to knock down survivin expression in the Ishikawa endometrial cancer cell line by recombinant plasmids producing survivin small hairpin RNA. Furthermore, the signal pathway that regulates survivin expression was investigated.RESULTS. Higher levels of survivin mRNA and protein expression were observed in endometrial adenocarcinomas than in atypical or normal endometrium. Immunohistochemical staining revealed that 83.3% (50 of 60) of endometrial adenocarcinoma samples, 55.0% (11 of 20) of atypical endometrium samples, and 25.0% (5 of 20) of normal endometrium samples were positive for survivin protein. Inhibition of survivin by RNA interference reduced cell proliferation and induced apoptosis in Ishikawa cells by down-regulating cyclin D1 and phosphorylated RB and activating caspase-3 and caspase-8. The authors also found that the MAPK pathway was a signal transduction pathway upstream of survivin. Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha) upregulated survivin protein expression by activating the MAPK pathway in endometrial cancer cells.CONCLUSIONS. Survivin is an attractive target for endometrial cancer treatment. Growth factors could regulate survivin expression by activating the MAPK pathway.