HSP47通过诱导CCL2表达促进膀胱癌血管形成的机制研究

新生血管在膀胱癌的发生、进展、转移和复发中起关键作用。热休克蛋白是调节肿瘤新生血管形成的重要分子伴侣。申请者前期发现：热休克蛋白HSP47在膀胱癌中高表达且与病人预后生存显著相关；体外体内功能实验证明HSP47促进膀胱癌细胞诱导的血管形成；初步的机制探索表明HSP47调节CCL2表达和ERK分子活性，抵制CCL2表达和ERK分子活性抑制了膀胱癌细胞诱导的血管形成；最后我们在人膀胱癌组织芯片中，证明HSP47与CCL2表达及微血管形成显著相关。由此我们提出HSP47通过诱导CCL2表达促进膀胱癌血管形成的科学假设。本项目拟在前期工作的基础上，进一步明确HSP47在膀胱癌血管形成中的作用，深入研究HSP47通过诱导CCL2表达促进膀胱癌血管形成的分子机制，同时探索HSP47抑制剂在膀胱肿瘤中的治疗效果。通过本项目，不但能完善膀胱癌血管形成的分子机制，也将为膀胱癌血管靶向治疗提供新思路和新靶点。

Neovascularization plays a key role in the occurrence, progression, metastasis and recurrence of bladder cancer. It is becoming clear that heat shock protein (HSP) is an important molecular chaperone for tumor neovascularization.Our previous studies indicated that HSP47 was highly expressed in bladder cancer and was significantly related to the overall survival of patients; Further, we proved that HSP47 promoted angiogenesis of bladder cancer cells by functional assays in vitro and in vivo; Preliminary studies on the mechanism showed that HSP47 regulated CCL2 expression and ERK activity. Inhibition of CCL2 and ERK decreased angiogenesis induced by bladder cancer cells; Finally, we proved that HSP47 is correlated with CCL2 expression and microvessel formation in bladder cancer tissue microarray. Thus, we proposed that HSP47 promotes angiogenesis through induction of CCL2 in bladder cancer. Based on the preliminary work, we intend to confirm the role of HSP47 in bladder cancer angiogenesis, study the mechanism of HSP47-promoted angiogenesis, and explore the effect of HSP47 in treating bladder tumor. This project will not only benefit to reveal the mechanism of bladder cancer angiogenesis, but also provide new insights and new target for anti-angiogenesis therapy of bladder cancer.