网膜脂肪细胞分泌MCP-1促进卵巢癌侵袭转移及顺铂耐药的机制研究

Epithelial ovarian cancer has the highest fatality rate in the female reproductive system tumors, in which extensive abdominal metastasis and chemotherapy resistance are the main reasons for treatment failure. Omentum is one of the earliest metastases sites of ovarian cancer, with a metastasis rate 37% -71%, while the intrinsic mechanism is unknown. .In the previous work, we co-cultured ovarian cancer cell lines with isolated omental fat cells and carried out adipokines chip screening. The results suggested that fat cell secretory protein MCP-1 may be involved in ovarian cancer metastasis and platinum-resistance..In this program, using the technologies of RNA interference, over-expression plasmid, gene expression microarray, tissue microarray (TMA) immunohistochemical technology, we aim at finding the intrinsic mechanism of MCP-1 promoting the metastasis and cisplatin resistance of ovarian cancer.we plan to validate the role of MCP-1 plays in ovarian cancer by blocking MCP-1 and inhibiting its receptor CCR2 expression in xenograft nude mice model. The TMA experiments will be performed to investigate whether the levels of MCP-1 and CCR2 expression will correlate with the chemotherapy response and survival of ovarian cancer patients. .This project will try to clarify the new mechanism that MCP-1 promotes ovarain cancer metastasis and platinum-resistant, and bring a new view to the research of metastasis and targeted drugs of ovarian cancer.

上皮性卵巢癌是致死率最高的女性生殖系统肿瘤，腹腔广泛转移及化疗耐药是治疗失败的主要原因。大网膜是卵巢癌最早的转移部位之一，转移率为37%-71%，但内在机理不明。申请者前期通过分离原代网膜脂肪细胞，与卵巢癌细胞共培养及脂肪因子芯片检测，发现分泌蛋白MCP1可能参与卵巢癌转移及促进铂类耐药。本项目拟利用RNA干扰、过表达质粒、基因表达谱芯片、免疫组织化学等技术在卵巢癌细胞、组织标本中探索MCP-1促进卵巢癌侵袭转移及顺铂耐药的内在机制，裸鼠移植瘤模型中探索阻断MCP-1及抑制其受体CCR2对卵巢癌侵袭转移和顺铂治疗反应的影响，并在卵巢癌组织芯片中探讨MCP-1与CCR2水平与患者化疗耐药和预后的相关性，以期揭示MCP-1参与卵巢癌转移和耐药的新机制，为卵巢癌转移及化疗耐药研究和靶向药物应用提供新思路。

上皮性卵巢癌患者确诊时多为晚期，伴有广泛的盆腹腔转移，大网膜是主要的转移灶，最终导致患者预后不佳。虽然腹腔内种植转移的机制研究很多，但是关于网膜在卵巢癌腹腔转移中的作用仍不清楚。本研究发现了卵巢癌大网膜转移的新机制：我们发现，MCP-1主要由大网膜脂肪细胞分泌。MCP-1与脂肪细胞的效应相同，都能引发卵巢癌体内外的侵袭表型以及耐药性等恶性表型。CCR2在卵巢癌细胞上高表达，CCR2的阻断能抵消MCP-1的促肿瘤细胞转移作用。另外，网膜转移灶可以在C57BL/CCL2-/-小鼠中减退，但是在C57BL/CCR2-/- 小鼠中没有变化。在机制上，我们发现，MCP-1能够激活 PI3K/AKT/mTOR/ HIF-1a和VEGF-A通路，而二甲双胍可以使肿瘤细胞生长减慢，腹膜转移灶减少，其作用主要通过抑制网膜脂肪细胞分泌MCP-1而实现。