卵巢癌肿瘤干细胞及上皮-间质转化中RhoC作用及分子机理解析

Ovarian cancer is one of the commonest women cancers, cancer stem cell and epithelial- mesenchymal transition (ETM) is involved in the anti-drug, recurrence and metastasis of ovarian cancer. A body of evidences indicates the similarity between the signal pathways of both EMT and RhoC. In our previous work, it was found that up- regulated RhoC expression was closely linked to carcinogenesis, dedifferentiation, metastasis and progression of ovarian cancer. RhoC knockdown can reduce the expression of ROCK I matrix metalloproteinase 9 and vascular growth factor with the weaker ability to migrate and invade in ovarian cancer cells. Here, we firstly plan to isolate ovarian cancer stem cells, establish its culture condition and observe the effects of altered RhoC expression on their aggressive phenotypes, including karyoplasmic ratio, proliferation, cell cycle, apoptosis, migration and invasion. The molecular mechanisms about invasion and metastasis of ovarian cancer stem cells will be investigated from the regulation of MMPs activity, lamellipodia and invapodia formation by RhoC. We also want to investigate the roles of RhoC in signal initiation and transcriptional regulation of nuclear target genes during EMT. If successful, the molecular mechanisms of metastasis, recurrence and anti-drug will be clarified using EMT and stem cell theories. The study will enrich the oncogenic roles of RhoC and related signal pathways in ovaraian cancer stem cell and EMT, and provide a novel target molecule for early diagnosis and late gene therapy of ovarian cancer.

卵巢癌是女性生殖器官常见恶性肿瘤，上皮-间质转化（EMT）和肿瘤干细胞是卵巢癌耐药、复发和转移的重要因素。研究发现，EMT过程中信号启动和传导与RhoC通路极其相似。前期工作结果提示，卵巢癌中RhoC 表达上调且与卵巢癌发生、转移、去分化和演进密切相关，卵巢癌细胞中RhoC 表达下调后ROCK-I、MMP-9和VEGF表达降低，且导致细胞迁徙和侵袭能力降低。本研究将从卵巢癌肿瘤干细胞分离和培养入手，观察RhoC对卵巢癌肿瘤干细胞核质比、增殖、细胞周期、凋亡、迁徙和侵袭的影响，从MMPs活性调节和伪足形成角度分析卵巢癌肿瘤干细胞侵袭和转移中RhoC作用分子机理。揭示卵巢癌细胞EMT中RhoC对细胞信号启动及细胞核内对转录因子作用靶基因的调控作用。本研究的顺利实施，可推动卵巢癌干细胞和EMT中RhoC作用分子机理研究，为卵巢癌早期诊断和晚期基因治疗提供新的分子靶点。

卵巢癌是女性生殖器官常见恶性肿瘤，上皮-间质转化（EMT）和肿瘤干细胞是卵巢癌耐药、复发和转移的重要因素。研究发现，EMT过程中信号启动和传导与RhoC通路极其相似。本研究将从卵巢癌肿瘤干细胞分离和培养入手，观察RhoC对卵巢癌肿瘤干细胞核质比、增殖、细胞周期、凋亡、迁徙和侵袭的影响，从MMPs活性调节和伪足形成角度分析卵巢癌肿瘤干细胞侵袭和转移中RhoC作用分子机理。揭示卵巢癌细胞EMT中RhoC对细胞信号启动及细胞核内对转录因子作用靶基因的调控作用。本研究的顺利实施，推动了卵巢癌干细胞和EMT中RhoC作用分子机理研究，为卵巢癌早期诊断和晚期基因治疗提供新的分子靶点。近年来microRNA是研究的热点，我们在课题项目资助过程中还研究了对RhoC具有调控作用的miRNAs，研究中发现miRNA-93-5p、miRNA-106可通过RhoC通路影响卵巢癌的发生发展。同时还发现miRNA-490-3p、miRNA-133b、miRNA-186对卵巢癌耐药性的影响，这些研究进一步在表观遗传的角度揭示了卵巢癌的发生发展机理，并为卵巢癌的诊断及治疗提供新的思路。