miR-183抑制骨肉瘤细胞自噬并增强其化疗敏感性的机制研究

项目名称： miR-183抑制骨肉瘤细胞自噬并增强其化疗敏感性的机制研究

项目编号： No.81502327

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 朱俊峰

作者单位： 中山大学

项目金额： 18万元

中文摘要： 化疗耐药已成为严重影响骨肉瘤患者治疗效果和预后的瓶颈。申请人以往研究表明：新辅助化疗后骨肉瘤组织中miR-183的表达明显增高，提示miR-183可能与骨肉瘤化疗有关，但其作用机制尚不明确。预实验表明：新辅助化疗后，对化疗反应好的组织miR-183表达明显高于化疗反应差者；裸鼠皮下骨肉瘤中的研究提示：抑制自噬能增强骨肉瘤的化疗敏感性；miR-183能够抑制骨肉瘤细胞自噬且增强其化疗敏感性，并证实miR-183的靶基因ATG5。由此，申请人提出miR-183增强骨肉瘤化疗敏感性的新机制，即miR-183靶向ATG5抑制自噬，进而增强骨肉瘤的化疗敏感性。本项目拟进一步在体外及裸鼠原位骨肉瘤模型中获得miR-183靶向ATG5抑制骨肉瘤自噬并增强化疗敏感性的可靠证据。本项目将阐明miR-183增强骨肉瘤化疗敏感性的作用及机制，为miR-183作为临床骨肉瘤化疗耐药的新靶点提供充分的科学依据。

中文关键词： 骨肿瘤；miRNA-183；骨肉瘤；化疗敏感性；自噬

英文摘要： Chemotherapy resistance has become a serious obstacle in therapeutic effect and prognosis.of osteosarcoma patients. Our previous study showed that increased expression level of miR-183 was observed in Osteosarcoma with neoadjuvant chemotherapy compared with that in paired biopsy without neoadjuvant chemotherapy. It is likely that chemotherapy could upregulate the expression level of miR-183 in Osteosarcoma, which could boost the sensitivity to preoperative chemotherapy in Osteosarcoma patients. However, further studies are necessary to elucidate the underlying mechanisms. Our preliminary experiments showed that miR-183 expression was significantly decreased in specimens from Osteosarcoma patients that showed a poor chemoresponse compared to those that responded well to chemotherapy. We also found that upregulation of miR-183 enhances chemosensitivity of Osteosarcoma cells in vitro and overexpression of miR 183 blocks anticancer drug induced autophagy in Osteosarcoma cells. Further studies showed that miR-183 downregulates ATG5-induced autophagy in osteosarcoma cells. The study on osteosarcoma models of nude mice showed that inhibition of autophagy could increase Osteosarcoma cells death, which suggest that inhibition of autophagy maybe enhance chemosensitivity of Osteosarcoma cells. Thus, we proposed new mechanism of miR-183 enhancing chemosensitivity of Osteosarcoma cells, that is: blocked ATG5-mediated autophagy by miR-183 enhances Osteosarcoma cell chemosensitivity. This project aims to further obtain reliable evidences of miR-183 inhibits autophagy via targeting ATG5 and enhance the chemosensitivity of in vitro and in orthotopic osteosarcoma nude mice model. And the correlation between miR-183 expression and autophagy will be verified in human clinical Osteosarcoma tissues. This project will be expected to elucidate the regulation and mechanism of miR-183 enhance chemosensitivity of Osteosarcoma cells, in order to provide more sufficient scientific basis for miR-183 as a new target in chemotherapy resistance of clinical Osteosarcoma patients.

英文关键词： bone tumor;miRNA-183;Osteosarcoma;chemosensitivity;autophagy