内脂素/胰岛素通过PI3K及ERK信号通路促进子宫内膜癌恶性进展的研究

Visfatin，as a newly identified adipocytokine which exerts insulin-mimetic effects, may serve as a link between metabolic syndrome and cancer. Visfatin is associated with malignant phenotype of tumors which are correlated with metabolic syndrome. However the exact mechanism of visfatin in endometrial cancer (EC) has not been reported yet. Moreover the research on visfatin and EC has not been presented yet. Insulin resistance is the core of Metabolic syndrome, which is closely associated with EC. Our previous study demonstrated that hyperinsulinemia was an independent risk factor of EC. However, insulin resistance dose not seem to be the whole story for EC carcinogenesis. The role of visfatin in cancer is growing to be concerned by researchers. Our previous research showed that the expression level of visfatin in EC serum and tissue was significantly increased when compared to the control. The expression of visfatin in EC patient with advanced stage was significantly decreased when compared to the patient with early stage. All those results indicated visfatin may play an important role in EC. In this project, we plan to focus on the following three fields. Firstly, enlarge the clinical sample to observe the clinical significance of visfatin expression in EC. Secondly in vitro and in vivo, we will investigate if visfatin promote EC cell growth through binding to insulin receptor or Nampt activity and then following the activation of the PI3K and ERK signaling pathway to promote cell growth and invasion. Also we will investigate the synergy effects of visfatin and insulin on EC. Finally, we will indicate if visfatin inhibition can become the therapeutic targets and sensitize EC to chemotherapy/radiotherapy in vitro and in vivo. This research will help us get a better understanding of the etiology and pathogenesis of EC and provide a theory basis for progression evaluation and the target therapy of EC.

内脂素为一种具有类胰岛素活性的新型脂肪因子,可能是连接代谢综合征(MS)与肿瘤的纽带,与多种MS相关性肿瘤的恶性表型有关，但作用机制不明。内脂素与子宫内膜癌(EC)的关系国内外未见报道。MS以胰岛素抵抗(IR)为核心,与EC密切相关,我们发现高胰岛素为EC独立危险因素,但不能完全解释EC发生,具有类胰岛素作用的内脂素日益受到重视。我们前期发现EC血清、组织中内脂素增高,且晚期高于早期,提示内脂素可能与EC恶性进展相关。本课题拟从三方面研究:①扩大样本研究内脂素表达与EC临床病理特征的关系;②体内、外实验观察内脂素是否与胰岛素受体直接结合和/或发挥Nampt活性，激活PI3K及ERK通路促进EC生长、转移及其与胰岛素有无协同/互补作用;③体内、外实验观察抑制内脂素能否成为EC治疗的新靶点及增加EC对放化疗敏感性。本研究有助于提高对EC发病机制的认识,为EC预后判断、靶向治疗提供理论基础。

子宫内膜癌（EC）是妇科三大恶性肿瘤之一，其发病率呈逐年上升趋势，其发病原因及机制不清。内脂素为一种新型脂肪因子,可能是连接代谢综合征(MS)与肿瘤的纽带,与多种MS相关性肿瘤的恶性表型有关。MS以胰岛素抵抗为核心,与EC密切相关,我们前期研究发现胰岛素、肥胖均为EC的独立危险因素，胰岛素通过 PI3K/Akt 和/或MEK/ERK 信号传导通路促进EC 细胞增殖和迁移， 抑制其凋亡。具有类胰岛素作用的内脂素可能与EC恶性进展相关，内脂素升高有可能是除胰岛素抵抗之外，连接MS与肿瘤的另一个关键点。本研究探讨内脂素在EC发生发展中的作用及其发挥作用的信号通路，以及内脂素与胰岛素是否具有协同、互补作用。本研究分为临床研究、体内、体外实验三部分：①EC患者血清内脂素水平及组织内脂素表达与EC发病风险及临床病理特征的相关性分析结果显示，血清内脂素水平是EC发病的独立风险因素，EC组织内脂素高表达与EC患者临床分期进展、深肌层浸润及不良预后相关。②体外实验证实内脂素能够促进细胞增殖、促进G1/S期进展、促进迁移及侵袭、抑制凋亡。内脂素通过PI3K/Akt、MAPK/ERK1/2信号通路促进子宫内膜癌恶性进展。PI3K抑制剂LY294002 及ERK抑制剂U0126能够抑制内脂素对子宫内膜癌恶性进展的促进作用。FK866能够抑制内脂素对EC细胞恶性进展的促进作用，抑制内脂素对信号通路的活化作用。且进一步研究证实内脂素能够通过EMT途径促进子宫内膜癌的迁移。内脂素与胰岛素协同促进EC细胞的增殖、周期、迁移及侵袭，抑制细胞凋亡。内脂素与胰岛素协同作用活化PI3K/Akt、MAPK/ERK1/2信号通路。③通过Ishikawa细胞构建裸鼠移植瘤模型，体内实验证实内脂素能够促进子宫内膜癌细胞系裸鼠移植瘤的生长，FK866能够抑制裸鼠移植瘤的生长，内脂素与胰岛素对裸鼠移植瘤的生长具有协同促进作用。本课题执行期间发表文章10篇，其中SCI文章6篇，培养博士研究生4名，硕士研究生5名，圆满达到课题预期效果。本研究对内膜癌发病机制的认识有了新的提高，为EC的评估预后提供新的分子生物学指标，抑制内脂素可能成为EC治疗的新靶点。