雄激素/胰岛素通过AR介导经PI3K/Akt—β-catenin通路影响子宫内膜癌发生发展的新机制

Both hormone and growth factor play a vital role in endometrial cancer (EC) tumorigenesis. However，it hasn’t been reported the mechanism of crosstalk between androgen and insulin signaling pathway in EC. Our previous study found that the serum androgen and insulin levels in patients with endometrial cancer (EC) were significantly increased when compared to control. There is a positive correlation between the serum androgen and insulin levels. Either androgen or insulin is an independent risk factor for EC. With insulin stimulation, androgen promotes EC cell with androgen receptor (AR) positive expression growth at a lower concentration. Insulin promoted EC proliferation through PI3K/Akt-β-catenin signaling pathway. The expression levels of AR、InsR、p-Akt、β-catenin in EC tissue increased when compare to control. The positive expression of AR in nuclear showed a co-localization and positive correlation with positive expression of β-catenin in nuclear. The above results indicate androgen and insulin may play a role in EC tumorigenesis through the cross-talk between the androgen/AR and insulin/PI3K/Akt-β-catenin signaling pathway, but the exact mechanism is still unclear. In this project, we plan to focus on the following three fields: First, we will enlarge the clinical sample to observe the alteration and clinical significance of androgen, insulin, and key proteins levels in androgen/insulin signaling pathway in EC. Second, in vitro and in vivo, we will investigate whether androgen can activate the insulin receptor signaling pathway or insulin can activate AR signaling pathway which stimulated EC growth and metastasis by cross-talk between these two signaling pathway. Finally, we will examine whether the interaction between AR and β-catenin is the core link between the androgen/insulin signaling pathway and their downstream target gene transcription. This research will help us get a better understanding of the etiology and pathogenesis of EC and provide a theory basis for individualized treatment and prevent recurrence of EC.

性激素与生长因子相互作用是子宫内膜癌（EC）重要致病原因，但雄激素与胰岛素信号通路交叉与EC研究尚未见报道。课题组研究发现：EC患者血清雄激素、胰岛素升高且呈正相关，均为EC独立危险因素；高胰岛素水平，低剂量雄激素即促进雄激素受体（AR）阳性EC细胞生长；胰岛素通过PI3K/Akt-β-catenin通路促进EC进展；EC组织AR、InsR、p-Akt、β-catenin表达升高，核内AR、β-catenin阳性表达呈共定位、正相关，提示EC中存在雄激素、胰岛素交联对话的基础。本课题拟扩大样本检测雄激素、胰岛素及通路关键蛋白水平，探讨二者相关性及与EC临床病理特征关系；体内、外实验探讨雄激素是否通过InsR激活PI3K通路，胰岛素是否激活AR通路，进而影响EC进展；AR、β-catenin相互作用是否为连接雄激素、胰岛素通路与下游靶基因转录枢纽。为认识EC发病机制、指导治疗提供重要理论依据

雄激素在子宫内膜癌（Endometrial Cancer，EC）中的作用越来越受到重视。目前研究发现，EC患者体内雄激素明显高于健康对照组人群，提示雄激素可能在EC的发生发展中发挥一定的作用。但雄激素与EC患者预后的关系不明且作用机制不清。人体内大部分睾酮是以与蛋白（性激素结合球蛋白和白蛋白）结合的形式存在，与白蛋白结合的睾酮和游离睾酮可以发挥生物学功能，称为生物活性睾酮，但现有研究仅关注了血清中总雄激素，本课题重点研究生物活性睾酮在EC中的作用及意义。我们从三方面研究：①临床研究：高浓度生物活性睾酮的EC患者，FIGO I+II期、无淋巴结转移、肌层浸润≤1/2和无宫颈受累的患者比例显著高于低浓度组且总生存时间要显著长于低浓度组患者（P＜0.05）。恶性程度高的EC者，AR阴性表达比例高于恶性程度低者，但无明显统计学意义。②体外实验：发现高浓度DHT（100nM）可显著抑制其迁移侵袭，但对细胞的增殖无明显作用。DHT可抑制上皮间充质转化过程，促进E-cadherin与β-catenin的结合，稳定细胞间黏附结构的稳定性；同时促进WNT通路负性调控因子GSK3β的表达而抑制β-catenin入核，从而发挥抑制转移的作用。③体内实验：成功建立EC尾静脉转移瘤模型，发现DHT处理后转移瘤小于对照组，但二者无统计学差异。因此，血清生物活性睾酮有可能成为EC患者发生及预后的生物学指标。本研究对EC病因学的认识具有重要的理论意义；对合并高雄激素EC患者的个体化靶向治疗及预防具有潜在指导作用和重要的转化医学意义。