【摘要】 越来越多研究表明转运RNA(t RNA)修饰与肿瘤进程有关。本研究首次探索了线粒体t RNA G37位甲基化修饰酶TRMT5(t RNA甲基转移酶5)在肝细胞癌发生发展中的作用。生物信息学和临床分析发现TRMT5在肝癌组织中高表达且与预后不良相关。体内外实验表明TRMT5敲低可诱导肝癌细胞代谢重编程，减弱肝癌细胞的增殖和转移能力。进一步研究发现TRMT5敲低降低了肝癌细胞内缺氧诱导因子1α(HIF-1α)的稳定性，进而抑制肝癌细胞生长与转移。此外，TRMT5敲低还导致肝癌细胞对阿霉素的敏感性增加。综上所述，本研究表明靶向TRMT5可以抑制肝癌进程并提升肝癌细胞对化疗药物的敏感性。因此，TRMT5是一个新的致癌候选基因，可以作为肝癌治疗的潜在靶点。更多还原

【Abstract】 Accumulating evidence has confirmed the links between transfer RNA(tRNA) modifications and tumor progression.The present study is the first to explore the role of tRNA methyltransferase 5(TRMT5), which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma(HCC) progression. Here, based on bioinformatics and clinical analyses, we identified that TRMT5 expression was upregulated in HCC, which correlated with poor prognosis. Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro, which may be partially explained by declined extracellular acidification rate(ECAR) and oxygen consumption rate(OCR). Mechanistically, we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1(HIF-1) signaling pathway by preventing HIF-1α stability through the enhancement of cellular oxygen content. Moreover, our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-1α. In conclusion, our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs. Thus, TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.更多还原