Harmine通过抑制HDACs酶活性促进RECK表达和抑制卵巢癌转移的分子机制

Harmine是一种中药提取物，可能作为类似HDACs抑制剂发挥抗肿瘤作用。RECK是新型基质金属蛋白酶抑癌基因，在多种恶性肿瘤低表达。前期研究证实Harmine可以抑制卵巢癌细胞增殖和迁移，预实验发现Harmine能促进RECK基因在卵巢癌细胞表达上调，但分子机理不明。文献报道RECK基因表达水平可因与HDACs相互作用而被抑制。基于前期研究，我们推测Harmine可能通过抑制HDACs乙酰化修饰，从而促进RECK转录和表达来抑制卵巢癌进展。本课题拟在卵巢癌标本检测HDACs、RECK的表达水平及其与病理分级、分期相关性；采用Harmine处理卵巢癌细胞株，观察其是否通过影响组蛋白的表观调控介导RECK表达，并抑制细胞增殖、迁移和侵袭；移植过表达或敲低HDACs/RECK的卵巢癌细胞至荷瘤模型，Harmine处理观察对瘤体存活、大小及进展影响，揭示Harmine抗卵巢癌的具体分子机制。

Harmine, an herbal extract, has been proved to exert anti-tumor effects as a HDACs inhibitor. RECK is a novel matrix metalloproteinase (MMPs) tumor suppressor gene, which is low expressed in various malignant tumors. Our previous studies have indicated that Harmine could inhibit the the proliferation and migration of ovarian cancer cells. We have also found that Harmine upregulated the expression of RECK gene in ovarian cancer cells, however, the underlying molecular regulation mechanism remains unclear. It has been shown that the expression level of RECK gene can be inhibited by interaction with HDACs. Based on these researches, we speculated that Harmine may inhibit ovarian cancer progression by regulating histone acetylation to promote the anti-oncogene RECK transcription and expression. This project aims to detect the expression of HDACs and RECK in ovarian cancer tissue and their correlation with pathological grade and stage. The ovarian cancer cell lines will be treated with Harmine, and whether Harmine could inhibit the proliferation, migaration and invasion of ovarian cancer cells via mediating the expression of RECK through histones epigenetic regulation were observed. Ovarian cancer cells with overexpression or knockdown of HDACs / Reck were transplanted to the tumor bearing model, and the effect of Harmine on the survival, size and development of tumor were observed. It is expected to elaborate the molecular mechanism of Harmine on anti-ovarian cancer effects.