LIN28B转录后调控PPM1D促进卵巢癌转移的机制研究

Cancer metastasis is an important prognostic factor for ovarian carcinoma. However, no effective therapeutic target has been developed for ovarian cancer metastasis. Our previous study demonstrated that Wip1, which is encoded by the gene PPM1D, inhibited metastasis in ovarian cancer. Moreover, Wip1 expression was found decreased in serous ovarian cancer tissues, which led to poor prognosis, and the down-regulation of Wip1 may be related to post-transcriptional regulation. Based on literature and database prediction, we revealed that there were potential binding sites of LIN28B in PPM1D mRNA. Further study indicated that LIN28B could inhibit Wip1 expression and promote invasion of ovarian cancer cells. These results suggested that LIN28B could bind to PPM1D mRNA, reduce Wip1 expression, thus contributing to metastasis in ovarian cancer. This study, at the levels of molecules、cells、animals and human clinical specimens, is aimed to explore the underlying mechanism of LIN28B-mediated post-transcriptional regulation of PPM1D and investigate the role of LIN28B/Wip1 signaling pathway in ovarian cancer metastasis. We look forwad to exploring a novel target for ovarian cancer metastasis and providing a new therapeutic direction for ovarian cancer.

肿瘤转移是影响卵巢癌患者预后的重要因素，但针对卵巢癌转移尚无高效的治疗靶点。在前期研究中我们发现PPM1D基因编码的磷酸酶Wip1可以抑制卵巢癌转移，并在浆液性卵巢癌组织中表达降低，导致患者预后较差，而Wip1的下调可能与转录后调控机制相关。文献检索及软件预测结果提示PPM1D mRNA上存在RNA结合蛋白LIN28B的潜在结合位点。进一步的实验结果表明LIN28B能够抑制Wip1蛋白的表达，并促进卵巢癌细胞的侵袭能力。以上结果提示我们LIN28B可能与PPM1D mRNA相结合，通过转录后调控机制，抑制Wip1表达，从而促进卵巢癌转移。本课题将从分子、细胞、动物、人体组织水平，明确LIN28B转录后调控PPM1D的机制，系统性地研究LIN28B/Wip1通路在浆液性卵巢癌转移中的作用。本项目的开展将为研究卵巢癌转移提供新的靶点，为卵巢癌治疗提供新的思路。