MARCH7调控自噬参与卵巢癌EMT的分子机制研究

Invasion and metastasis usually occurs in ovarian cancer. However, the mechanism is not clear. MARCH7 is a member of the ubiquitin E3 ligase family. Previous study demonstrates that MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding. Our study finds that MARCH7 promotes ovarian tumor growth and invasion. However, the underlying mechanism needs further research. Our preliminary experiments found MARCH7 can regulate of LC3-II expression and TGF-β-SMAD2/3 signaling pathway reporter activity. At the same time, we found that MARCH7 interacted with TGFBR2. Based on clinical, cellular and animal experimental research, we will explore MARCH7 regulate EMT mediated by cellular autophagy through TGF-β-SMAD2/3 signaling pathway. This project focuses on the mechanism of autophagy, metastasis and invasion in ovarian epithelial carcinoma. Our findings will provide new diagnosis and treatment of ovarian cancer.

卵巢上皮性癌极易发生转移和侵袭。发生转移的患者预后极差，而目前其机制尚不清楚。E3泛素连接酶MARCH7是膜相关锌指蛋白家族（RING-CH）的一员。目前研究发现MARCH7参与微管蛋白泛素化。我们的研究发现MARCH7和卵巢癌的发生、发展有关。但其机制有待进一步研究。我们前期预实验发现MARCH7可以调控自噬分子LC3-II表达；MARCH7可以调控TGF-β-SMAD2/3信号通路reporter活性；同时我们发现MARCH7可以和TGFBR2相互作用。本研究拟从临床、细胞和动物实验三个层面研究MARCH7通过TGF-β-SMAD2/3通路对卵巢癌细胞自噬的调控参与卵巢癌EMT（上皮间质转化）的作用，从而调控卵巢癌转移和侵袭。本项目对卵巢上皮性癌自噬、转移和侵袭的机理以及寻找新的诊疗等具有重要的理论和实际意义。

E3泛素连接酶MARCH7是膜相关锌指蛋白家族（RING-CH）的一员。目前研究发现MARCH7参与微管蛋白泛素化。我们的研究发现MARCH7和卵巢癌的发生、发展有关。但其机制有待进一步研究。我们探讨 MARCH7 对卵巢癌自噬和 EMT 的调控，以及 MARCH7 通过 TGF-β-SMAD2/3 通路调控卵巢癌自噬和 EMT 及其可能机制。我们发现：MARCH7和长链非编码RNA malat1相互作用，激活TGFb/smad2-3通路，促进卵巢癌的自噬、侵袭和转移；ATG7是 MARCH7的内源性竞争RNA； MALAT1和ATG7相互调节依赖miR-200a；MARCH7和TGFBR2相互作用；TGF-β-SMAD2/ 3通路通过直接调控MALAT1调控MARCH7和ATG7；MARCH7调节TGF-β诱导的自噬，迁移和侵袭miR-200a通过靶向MARCH7调节TGF-β诱导的自噬，迁移和侵袭。MARCH7是卵巢癌潜在的治疗靶点和生物学标记物。