转瞬即逝的受体电位melastatin 8（TRPM8）在前列腺和乳腺癌等实体肿瘤中发挥关键作用。但在肝细胞癌（HCC）中TRPM8的作用及其潜在的分子机制仍大多未知。本研究首次系统研究了TRPM8在HCC中的功能作用。发现TRPM8的表达水平在HCC中显著上调，与更差的临床病理特征呈正相关。功能研究表明，药物抑制或基因下调TRPM8可以改善体内和体外的肝癌形成。从机制上讲，TRPM8在HCC的致癌作用至少部分是通过影响线粒体功能实现的。TRPM8可以通过诱导染色质结构和组蛋白修饰类型的变化来调节核小体相关分子-小核糖核酸，H/ACA盒子55（SNORA55）的表达。这些数据表明，在TRPM8触发的HCC中，SNORA55作为桥梁分子可以从细胞核迁移到线粒体，并通过靶向ATP5A1和ATP5B影响线粒体功能，发挥致癌作用。本研究揭示了TRPM8在HCC中诱导核和线粒体功能障碍的强有力致癌作用，以及为HCC提供了潜在的治疗靶点。 ©2023。作者在Springer Nature America，Inc.独家许可下发表。

Transient receptor potential melastatin 8 (TRPM8) play crucial roles in solid tumors such as prostate and breast cancers. But the role of TRPM8 in hepatocellular carcinoma (HCC) and its underlying molecular mechanisms remain largely unknown. In this study, the functional roles of TRPM8 in HCC were systematically investigated for the first time. It was found that the expression level of TRPM8 was significantly upregulated in HCC, which was positively correlated with the worse clinicopathological characteristics. Functional studies revealed that pharmacological inhibition or genetic downregulation of TRPM8 ameliorated hepatocarcinogenesis in vitro and in vivo. Mechanistically, the oncogenic role of TRPM8 in HCC was at least partially achieved by affecting mitochondrial function. TRPM8 could modulate the expression of nucleolar relative molecule-small nucleolar RNA, H/ACA box 55 (SNORA55) by inducing transformation of chromatin structure and histone modification type. These data suggest that as a bridge molecule in TRPM8-triggered HCC, SNORA55 can migrate from nucleus to mitochondria and exert oncogenic role by affecting mitochondria function through targeting ATP5A1 and ATP5B. Herein, we uncovered the potent oncogenic role of TRPM8 in HCC by inducing nuclear and mitochondrial dysfunction in a SNORA55 dependent manner, and provided a potential therapeutic target for HCC.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.