文章：

TRPM8通过诱导SNORA55介导的核-线粒体通讯促进肝细胞癌进展

TRPM8 promotes hepatocellular carcinoma progression by inducing SNORA55 mediated nuclear-mitochondrial communication 

原文发布日期：2023-01-06

英文摘要：

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. 

摘要翻译： 

瞬时受体电位melastatin 8（TRPM8）在前列腺癌和乳腺癌等实体肿瘤中起关键作用，但其在肝细胞癌（HCC）中的功能及潜在分子机制尚不明确。本研究首次系统探讨了TRPM8在HCC中的功能作用，发现TRPM8在HCC中表达显著上调，且与不良临床病理特征呈正相关。功能研究表明，药理学抑制或遗传学下调TRPM8可在体内外改善肝癌发生。机制上，TRPM8的致癌作用至少部分通过影响线粒体功能实现：它通过诱导染色质结构重构和组蛋白修饰类型变化，调控核仁相关分子——H/ACA框55小核仁RNA（SNORA55）的表达。这些数据表明，作为TRPM8触发HCC的桥梁分子，SNORA55可从细胞核迁移至线粒体，通过靶向ATP5A1和ATP5B影响线粒体功能进而发挥致癌作用。本研究揭示了TRPM8通过SNORA55依赖性方式诱导核与线粒体功能障碍，从而在HCC中发挥强效致癌作用，为HCC治疗提供了潜在靶点。

原文链接：

TRPM8 promotes hepatocellular carcinoma progression by inducing SNORA55 mediated nuclear-mitochondrial communication