Li Weiwei, Xie Ruiwang, Chen Huaying, Lin Junyu, Zhong Minjie, Zhang Junsi, Zheng Shengkai, Jiang Cen, Chen Xiangjin, Xu Sunwang
Department of Thyroid and Breast Surgery, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, China.
Cell Death Dis. 2025 May 14;16(1):378. doi: 10.1038/s41419-025-07716-8.
N7-methylguanosine (mG) modification of transfer RNA (tRNA) is essential for the biological functions of tRNAs and has been found to play a regulatory role in a variety of human cancers. However, the biological function of METTL1-mediated mG tRNA modification in papillary thyroid cancer (PTC) is unclear. Here, we found that METTL1 is significantly upregulated in PTC tissues compared to normal control tissues and is associated with poor PTC prognosis. Functional analysis confirmed that METTL1 promotes the proliferation and metastasis of PTC cells in a manner dependent on its tRNA methyltransferase activity. Mechanistically, METTL1 knockdown leads to a decrease in the abundance of certain mG-modified tRNAs, which suppresses the mG tRNA modification-mediated codon-specific translation of TNF-α. Furthermore, exogenous supplementation with TNF-α partially reversed the decrease in the proliferation and metastasis of PTC cells induced by METTL1 deletion. Positive correlations between METTL1, WDR4, and TNF-α expression, which affect the proliferation and metastasis of PTC, were confirmed via analysis of microarrays containing PTC tissues. These results demonstrate the oncogenic role of METTL1-mediated mG tRNA modification in regulating codon-specific translation efficiency in PTC and suggest that targeting METTL1 may be a promising therapeutic approach for overcoming PTC progression by inhibiting PTC cell proliferation and metastasis.
转运RNA（tRNA）的N7-甲基鸟苷（mG）修饰对于tRNA的生物学功能至关重要，并且已发现在多种人类癌症中发挥调节作用。然而，METTL1介导的mG tRNA修饰在甲状腺乳头状癌（PTC）中的生物学功能尚不清楚。在此，我们发现与正常对照组织相比，METTL1在PTC组织中显著上调，并且与PTC预后不良相关。功能分析证实，METTL1以依赖其tRNA甲基转移酶活性的方式促进PTC细胞的增殖和转移。机制上，METTL1敲低导致某些mG修饰的tRNA丰度降低，从而抑制了mG tRNA修饰介导的TNF-α密码子特异性翻译。此外，外源性补充TNF-α部分逆转了METTL1缺失诱导的PTC细胞增殖和转移的减少。通过分析包含PTC组织的微阵列，证实了METTL1、WDR4和TNF-α表达之间的正相关，它们影响PTC的增殖和转移。这些结果证明了METTL1介导的mG tRNA修饰在调节PTC中密码子特异性翻译效率方面的致癌作用，并表明靶向METTL1可能是通过抑制PTC细胞增殖和转移来克服PTC进展的一种有前景的治疗方法。
