circ_0000285/miR-599/TGF-β2轴调控自噬介导骨肉瘤化疗耐药的机制研究

化疗耐药是骨肉瘤复发转移的主要原因之一。多项研究表明circRNA在多种肿瘤中异常表达，广泛参与肿瘤自噬、凋亡、侵袭转移及化疗耐药等过程。本课题组前期研究发现circ_0000285在骨肉瘤肿瘤组织中高表达，作为竞争内源性RNA吸附miR-599上调TGF-β2的表达，从而影响骨肉瘤细胞的增殖和迁移。文献报道TGF-β2能诱导自噬发生，课题组前期研究发现自噬参与调控骨肉瘤化疗敏感性。但circ_0000285是否介导自噬影响骨肉瘤的化疗敏感性尚未明确，因此我们提出：在骨肉瘤化疗中circ_0000285/miR-599/TGF-β2轴调控细胞自噬水平，影响肿瘤细胞对化疗药物的敏感性。本课题拟在既往研究骨肉瘤中circRNA和自噬作用的基础上，深入研究circ_0000285对骨肉瘤化疗中调控自噬的机制，明确骨肉瘤化疗耐药的关键调控靶点，为化疗联合靶向治疗提供新的理论依据。

The drug resistance of osteosarcoma chemotherapy is one of the main reasons for relapse metastasis. A number of studies have shown that circRNA is abnormally expressed in a variety of tumors and is widely involved in biological processes such as autophagy, apoptosis, invasion and metastasis, and chemotherapy resistance. Our previous study found circ_0000285 in osteosarcoma is highly expressed in tumor tissues, and as a competitive adsorption of miR - 599 raised TGF-β2 endogenous RNA expression, which affects the osteosarcoma cells proliferation and migration. It has been reported in the literature that TGF-β2 can induce autophagy, and previous studies by our group have found that autophagy is also involved in regulation of osteosarcoma chemotherapy sensitivity. Whether circ_0000285 affects osteosarcoma cells mediated autophagy chemotherapy sensitivity is unclear. Based on this, we propose that circ_0000285/ miR-599 /TGF-β2 axis regulates the level of autophagy during the chemotherapy of osteosarcoma and affects the sensitivity of tumor cells to chemotherapy drugs. This study intends to further study the mechanism of circ_0000285 on the regulation of autophagy in osteosarcoma chemotherapy on the basis of previous studies on circRNA and autophagy in osteosarcoma, to identify the key regulatory targets of osteosarcoma chemoresistance, and to provide a new theoretical basis for chemotherapy combined with targeted therapy.