BMPR2介导非经典信号通路在骨肉瘤药耐药过程中的功能及机制研究

Osteosarcoma is the most common primary malignant bone tumor in children and adolescents. Drug resistance is still one of the failure reasons for treating osteosarcoms. Although BMP signaling pathway is a hotspot, and the canonical signaling pathway in osteosarcoma draws most attention, research about the role of non-canonical signaling pathway in osteosarcoma progression is rareness. Our previous results showed that osteosarcoma patients of high level of BMPR2 had poorer clinical prognosis. The level of BMPR2 in osteosarcoma tissues is related with the level of autophagy protein and LIMK2. At the same time, we confirmed that the BMPR2 was more highly expressed in drug-resistance cell line MG63-Dox than in normal MG63 cells. These results indicated that BMPR2 regulated drug resistance in osteosarcoma. However, the exactly mechanism is not clear. Based on the above results, the project intend to investigate non-canonical signaling pathway downstream of BMPR2 in regulating drug resistance of osteosarcoma. Through in vitro and in vivo as well as clinical sample analysis, we will obtain the target proteins and corresponding signaling pathways which will benefit for osteosarcoma targeted therapy and individual therapy.

骨肉瘤是儿童和青少年最常见的原发恶性骨肿瘤，化疗耐药仍是治疗骨肉瘤失败的主要原因之一。BMP信号通路是当前研究的热点，但在骨肉瘤中主要集中在经典BMP信号通路，而对非经典BMP信号通路的研究较少。我们前期通过公共芯片数据库分析发现BMPR2的表达水平高的骨肉瘤患者预后较差，进一步分析发现BMPR2的表达水平与自噬标志蛋白及LIMK2表达密切相关，而自噬和LIMK2与肿瘤耐药相关。并且前期细胞学实验也发现，耐药骨肉瘤细胞株MG63-Dox的BMPR2的表达比正常MG63增高，提示BMPR2参与调控骨肉瘤的耐药，但是具体机制尚未明确。而本项目拟从BMPR2下游的非经典信号通路入手，通过细胞实验、动物实验和临床标本多重验证，得到BMPR2调控骨肉瘤耐药的分子机制，从而为骨肉瘤的治疗以及个体化治疗奠定基础。

骨肉瘤是儿童和青少年最常见的原发恶性骨肿瘤，化疗耐药仍是治疗骨肉瘤失败的主要原因之一。BMP信号通路是当前研究的热点，但在骨肉瘤中主要集中在经典BMP信号通路，而对非经典BMP信号通路的研究较少。在本项目中，通过高通量测序筛选和验证，发现BMPR2在人类多种肿瘤中表达异常；BMPR2表达增高影响骨肉瘤患者的预后；BMPR2调控巨噬细胞分化通路和单核细胞极性通路的建立或维持；BMPR2表达与免疫标记集的相关，骨肉瘤中BMPR2表达增加与骨肉瘤中CD8+ T细胞、单核细胞和M2巨噬细胞的免疫浸润减少及预后不良相关。同时，我们发现cicrRNA LPAR1在骨肉瘤耐药过程中发挥着重要的作用，作为ceRNA调控下游靶基因影响血管内皮细胞增殖及巨噬细胞极化。目前在国内外文献中未见报道，在后续工作，将进一步明确cicrRNA LPAR1和骨肉瘤耐药之间的相关性及其中的分子机制，为骨肉瘤的靶向治疗和免疫治疗提供分子生物学基础。