Evidence That Leptin Through STAT and CREB Signaling Enhances Cyclin D1 Expression and Promotes Human Endometrial Cancer Proliferation
Evidence That Leptin Through STAT and CREB Signaling Enhances Cyclin D1 Expression and Promotes Human Endometrial Cancer Proliferation
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DOI：
10.1002/jcp.21622
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发表时间：
2009-03-01
影响因子：
5.6
通讯作者：
Ando, Sebastiano
中科院分区：
文献类型：
--
作者：
Catalano, Stefania;Giordano, Cinzia;Ando, Sebastiano
肥胖是绝经前后妇女子宫内膜癌的危险因素。瘦素是一种脂肪细胞源性激素，除了控制体重稳态外，还参与多种生物学作用。最近的研究表明，瘦素通过STAT/MAPK和Akt通路促进子宫内膜癌的生长和侵袭，但其分子机制仍有待阐明。为了了解瘦素在调节子宫内膜癌细胞增殖中的作用，我们已经证明瘦素处理减少了G 0/G1期细胞的数量，同时增加了S期细胞的数量。这种作用与细胞周期蛋白D I的上调以及细胞周期蛋白依赖性激酶抑制剂p2 I（WAF 1/Cip 1）的下调有关。突变研究、电泳迁移率改变和染色质免疫沉淀分析显示，在石川子宫内膜癌细胞中，瘦素诱导的细胞周期蛋白D1表达需要细胞周期蛋白D1启动子内的信号转导和转录激活因子3（STAT 3）和环腺苷酸反应元件（CRE）结合蛋白基序。RNA干扰沉默STAT 3和CREB基因表达可逆转瘦素对细胞周期蛋白D I表达和细胞增殖的上调作用。这些结果支持了STAT 3和CREB在导致石川细胞增殖的瘦素信号通路中发挥重要作用的假设。细胞，从而建立肥胖和子宫内膜肿瘤发生之间的直接关联。
Obesity is a risk factor for endometrial cancer in pre- and post-menopausal women. Leptin, an adipocyte-derived hormone, in addition to the control weight homeostasis, is implicated in multiple biological actions. A recent study demonstrated that leptin promotes endometrial cancer growth and invasiveness through STAT/MAPK and Akt pathways, but the molecular mechanism involved in such processes still needs to be elucidated. In an attempt to understand the role of leptin in regulating endometrial cancer cells proliferation, we have demonstrated that leptin treatment reduced the numbers of cells in G0/G1-phase while increased cell population in S-phase. This effect is associated with an up-regulation of cyclin D I together with a down-regulation of cyclin-dependent kinase inhibitor p2I(WAF1/Cip1). Mutagenesis studies, eletrophoretic mobility shift, and chromatin immunoprecipitation analysis revealed that signal transducers and activators of transcription 3 (STAT3) and cyclic AMP-responsive element (CRE) binding protein motifs, within cyclin D I promoter, were required for leptin-induced cyclin D1 expression in Ishikawa endometrial cancer cells. Silencing of STAT3 and CREB gene expression by RNA interference reversed the up-regulatory effect of leptin on cyclin D I expression and cells proliferation. These results support the hypothesis that STAT3 and CREB play an important role in leptin signaling pathway that leads to the proliferation of Ishikawa. cells, thus establishing a direct association between obesity and endometrial tumorogenesis.