散发性卵巢癌BRCA1甲基化诱导化疗敏感性的新机制

If the hereditary ovarian cancer chemosensitivity owes to BRCA1 (breast-ovarian cancer gene 1,BRCAl)mutation,which inhibit the restore when chelate DDP and DNA leading to cell growth stasis.We suppose that whether we can improve chemotherapy by changing gene function in charging of changing gene construction in sporadic ovarian cancer.Our previous study and expreriment in advance approved the hypothesis.That was as the followings:BRCA1 hypermethylated in sporadic ovarian cancer tissues and cells.All the same,BRCA1 hypermythelation related to TGF-β1 pathway.Now,based on the previous study,we will test the expression of TGF-β1 pathway in chemosensitive and chemoresistant cells,respectively; test the regulation between TGF-β1 and BRCA1;to explore how the regulation effects the DDP sensitivity in ovarian cancer cells.Our aim is to make sure that BRCA1 negatively regulates TGF-β1 expression,improving the chemosensitivity.The study may strengthen our knowledge of DDP chemoresistance and afford stable experiment proof for the targeted therapy.

如果遗传性卵巢癌化疗敏感的原因是乳腺癌/卵巢癌易感基因（BRCA1）突变使得细胞DNA与顺铂螯合时不能得到修复而造成细胞生长停滞，那么在临床上对化疗有良好反应的、部分未发生BRCA1突变的非遗传性（散发性）卵巢癌的化疗敏感机制是否可以不通过BRCA1基因结构、而是通过其功能改变以达成与BRCA1基因突变一样的化疗增敏效果？课题组前期研究和预实验初步证实了上述推测：散发性卵巢癌组织和细胞中存在BRCA1启动子甲基化；BRCA1甲基化与TGF-β1信号通路存在相关性。本项课题在预实验的基础上，检测卵巢癌顺铂耐药与敏感细胞的TGF-β1通路表达；验证TGF-β1与BRCA1相互调控作用；探讨TGF-β1与BRCA1之间的调控对顺铂敏感性的影响，旨在证实BRCA1甲基化通过负性调控TGF-β1，增强卵巢癌顺铂化疗敏感性。研究将深化对卵巢癌顺铂化疗耐药的理解，为卵巢癌靶向治疗提供坚实的实验依据。

上皮性卵巢癌（卵巢癌）病死率居妇科恶性肿瘤之首，寻找疾病早期诊断方法和晚期阶段的化疗增敏策略是当今妇科肿瘤领域十分重要的研究课题。乳腺癌/卵巢癌易感基因（BRCA1）突变使得细胞DNA与顺铂螯合时不能得到修复而造成细胞生长停滞，从而使未发生BRCA1突变的非遗传性（散发性）卵巢癌的化疗敏感性增强。课题通过以下方面探讨BRCA1在卵巢癌化疗过程中的增敏作用及其作用机制：（一）通过基因芯片技术筛选出BRCA1化疗增敏关键通路TGF-β1，并检测到TGF-β1/Smad3通路在卵巢癌化疗敏感性细胞中呈差异性表达；（二） 体外试验发现TGF-β1促进卵巢癌细胞增殖，其表达水平与卵巢癌细胞化疗敏感性负相关，体内试验证实，TGF-β1促进裸鼠荷瘤生长，降低其对DDP化疗的敏感性；（三）BRCA1与TGF-β1存在互相抑制作用，BRCA1通过与下游的Smad3结合发挥其对TGF-β1的调控作用；研究结论将深化对卵巢癌顺铂化疗耐药的理解，为卵巢癌靶向治疗提供坚实的实验依据。