RNA(m5C)甲基转移酶NSUN2通过FABP5调控脂肪酸代谢促进骨肉瘤恶性增殖的机制研究

RNA修饰与骨肉瘤恶性增殖密切相关，然而RNA(m5C)甲基化修饰在骨肉瘤中的作用尚不明确。我们前期研究发现：m5C甲基转移酶NSUN2在骨肉瘤中高表达，且可调控骨肉瘤细胞恶性增殖及mRNA的m5C修饰；m5C测序发现，在敲低NSUN2的骨肉瘤细胞中，FABP5的m5C峰度降低，脂肪酸代谢通路富集显著；NSUN2可调控FABP5的表达和稳定性，以及脂肪酸代谢；干扰FABP5抑制骨肉瘤增殖。我们据此推测：NSUN2可能通过m5C修饰影响FABP5表达，调控脂肪酸代谢，进而促进骨肉瘤恶性增殖。本项目拟探讨m5C修饰与骨肉瘤的临床相关性，通过细胞和动物模型明确NSUN2及FABP5调控骨肉瘤恶性增殖的作用；阐明NSUN2通过m5C修饰调控FABP5的mRNA稳定性的机制；解析NSUN2通过FABP5调控骨肉瘤脂肪酸代谢及恶性增殖的机制。本项目将为骨肉瘤恶性增殖的机制研究拓展新思路。

RNA modification is closely related to the malignant proliferation of osteosarcoma, however, the role of RNA(m5C) methylation in osteosarcoma remains unclear. Our previous study found that NSUN2 was highly expressed in osteosarcoma cells, and could regulate the malignant proliferation of osteosarcoma cells and m5C methylation of mRNA. m5C sequencing results displayed that NSUN2-knockdown osteosarcoma cells showed lower m5C peak of FABP5 mRNA and significant enrichment of fatty acid metabolic pathway when compared with the control. Morever, NSUN2 could regulate the mRNA stability and expression of FABP5 and the fatty acids metabolism. And down-regulation of FABP5 inhibited the cell proliferation of osteosarcoma. Thus we hypothesize that NSUN2 may regulate the expression of FABP5 through m5C methylation, further regulating and fatty acids metabolism and promoting the malignant proliferation of osteosarcoma. This project will provide a new approach for revealing the mechanism of malignant proliferation of osteosarcoma.