胰岛素受体后信号通路介导IGFBP-rP1对子宫内膜样腺癌的抑制作用

Metabolic syndrome, characterized by insulin resistance, is closely associated with increased risk of endometrioid adenocarcinoma. insulin like growth factor binding protein-related protein 1(IGFBP-rP1)，higher affinity to insulin than other IGFBPs, is involoved in the body’s resistance to insulin and takes part in genesis and development of some malignant tumors. Our previous studies have disclosed that it plays a supressive role in endometrioid adenocarcinoma and is associated with insulin resistance. But the mechanism has not been clear yet. We speculate that IGFBP-rP1 may play the suppresive role via insulin postreceptor signal pathway associated with insulin resistance. So, to verify this hypothesis, by using immunoblot, immunoprecipitation, cell transfection and fluorescene imaging techniques,firstly,we will further study the specific roles of IGFBP-rP1 in endometrioid adenocarcinoma. We will detect the expression of IGFBP-rP1 in serum and tumor tissues in endometrioid adenocarcinoma patients and investigate the relationship with clinicopathological features, especially with metabolic syndrome such as obesity, diabetes, hypertension, insulin resistance and the effect of IGFBP-rP1 on proliferation, migration, adhension, invasiveness and apoptosis of endometrial cancer cells and on tumor formation in nude mice through the experiments in Vitro and in Vivo. And , secondly,the alteration of insulin postreceptor signal pathway such as activation of insulin receptor substrate and PI3K/Akt signal pathway as well as Ras/MAPK signaling will be explored during the above process influenced by IGFBP-rP1.And lastly, effects of blockage of IGFBP-rP1 induced activation of this insulin postreceptor signal pathway on proliferation and apoptosis of endometrial cancer cells will be observed. The present project will contribute greatly to revealing the pathogenous process of endometrioid adenocarcinoma associated with metabolic syndrome and providing new idea to effective prevention and treatment of endometrioid adenocarcinoma.

以胰岛素抵抗为特征的代谢综合征与子宫内膜样腺癌密切相关，IGFBP-rP1因与胰岛素有很强的结合力参与机体胰岛素抵抗，我们前期研究发现，IGFBP-rP1在子宫内膜样腺癌中发挥抑癌功能，与胰岛素抵抗有关，但其作用机制还有待进一步探讨。为此，我们提出假说：IGFBP-rP1可能通过胰岛素受体后信号通路参与子宫内膜样腺癌的发生。为验证该假说，我们拟采用免疫沉淀、细胞转染、RNA干扰、肿瘤活体成像等技术，通过体内体外实验，从血清、细胞、组织以及动物整体水平等多方面探讨IGFBP-rP1在子宫内膜样腺癌发生中的重要作用，明确IGFBP-rP1是否通过胰岛素受体后信号通路参与胰岛素抵抗来抑制子宫内膜样腺癌的发生以及阻断该通路对子宫内膜腺癌细胞增殖凋亡的影响。本研究将从IGFBP-rP1这个新视点为揭示以胰岛素抵抗为核心的代谢综合征诱发子宫内膜样腺癌的机制奠定基础，为子宫内膜样腺癌的有效防治提供新思路

随着医疗水平的不断提高，子宫内膜癌正朝着非手术治疗的方向发展。课题组从代谢综合征出发，发现IGFBP-rP1可通过抑制胰岛素受体后PI3K/Akt通路发挥抑癌作用，IGFBP-rP1的高表达可抑制子宫内膜癌细胞（Ishikawa，hec-1a）的增殖、迁移和侵袭；课题组开展的一项前瞻性研究发现，甲地孕酮联合二甲双胍治疗早期内膜癌缓解率高，复发率低，并伴有IGFBP-rP1的表达升高，进一步说明IGFBP-rP1可作为内膜癌新的治疗靶点；IR-A（胰岛素受体A）/IGF-1R（胰岛素样生长因子-1受体）可通过激活PI3K/AKT和ERK通路诱导子宫内膜癌细胞的多基因表型，敲低内源性IR-A或IGF-1R表达可降低子宫内膜癌细胞的迁移和侵袭能力，促进细胞凋亡，抑制EMT，从而抑制肿瘤生长，且同时下调IR-A和IGF-1R可出现协同效应，因此，靶向IR-A和IGF-1R也可成为内膜癌治疗的新靶点。