KLF12调控雄激素代谢酶及其受体信号通路促进子宫内膜癌增殖的机制研究

子宫内膜癌严重危害女性健康。研究发现除雌激素外，雄激素代谢酶及雄激素受体在子宫内膜癌组织中表达异常，并与子宫内膜癌发生发展有关。我们已证实转录因子KLF12高表达促进子宫内膜癌增殖，但作用的分子机制仍不清楚。我们新发现KLF12可调节间质细胞和上皮细胞中雄激素代谢酶芳香化酶和5α还原酶1的活性；KLF12抑制雄激素受体在上皮细胞的表达，并促进子宫内膜癌细胞增殖。由此推测子宫内膜癌组织中KLF12同时调控雄激素代谢酶和雄激素受体的表达，这可能是子宫内膜癌发生发展的新机制。本项目将采用高通量测序、分子生物学、生物化学和动物模型等技术，阐明KLF12通过调控雄激素代谢酶及雄激素受体的表达促进子宫内膜癌增殖的分子新机制，为评估KLF12分子及下游通路是否可以作为子宫内膜癌临床治疗的新靶点提供理论依据。

Endometrial cancer is a serious threat to women's health. It is now evident that androgen and its receptor, androgen receptor (AR) other than estrogen, are abnormally expressed in patients' tissues, and associated with the development of endometrial cancer. We have demonstrated that the transcription factor KLF12 promotes the proliferation of endometrial cancer, but the molecular mechanism remains largely unknown. Recently, we show that KLF12 regulates the activity of aromatase and 5α reductase 1 in stromal cells and epithelial cells, respectively. KLF12 inhibits AR expression in epithelial cells, to promote the proliferation of endometrial cancer cells. Based on these strong preliminary data, we hypothesize that KLF12 regulates androgen metabolizing enzymes and AR expression, which may be a new mechanism of endometrial cancer development. In this project, we will utilize research techniques of high-throughput sequencing, molecular biology and biochemistry in combination with animal model to uncover the novel molecular mechanism underlying KLF12 regulating androgen metabolizing enzymes and androgen receptor signaling pathways to promote endometrial carcinoma proliferation. Our study will provide a theoretical basis for evaluating whether KLF12 and its downstream pathways can serve as new targets for clinical treatment of endometrial cancer.