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

Cancer Gene Therapy volume 30, pages 738–751 (2023)Cite this article

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Abstract

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.

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Fig. 1: TRPM8 was significantly upregulated in HCC tissues and cell lines.
Fig. 2: TRPM8 knockout inhibited hepatocarcinogenesis and led to morphological changes of nuclei and mitochondria in DEN-induced HCC models.
Fig. 3: Pharmacological inhibition of TRPM8 channel activity inhibited hepatocarcinogenesis in vitro and in vivo.
Fig. 4: TRPM8 knockdown downregulated the expression of nucleolar relative molecule-SNORA55 by influencing chromosome structure and histone modifications.
Fig. 5: SNORA55 can migrate from nucleus to mitochondria.
Fig. 6: SNORA55 exert oncogenic role in HCC by affecting mitochondria function.
Fig. 7: SNORA55 is required for TRPM8-triggered hepatocarcinogenesis.
Fig. 8: Graphic abstract of the study.

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Data availability

All relevant data are available from the authors upon reasonable request. Supplementary information is available at (journal name’s) website.

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Acknowledgements

The authors want to thank all of the staffs of the Medical Experimental Research Center, The Second Xiangya Hospital of Central South University, for providing the research platform. We also want to thank the Department of Pathology of The Second Xiangya Hospital for its contribution to section preparation and pathological analysis.

Funding

This work was supported by the National Natural Science Foundation of China (81272475 and 81670111), Hunan Provincial Key Research and Development Program (2019SK2242) and the platform funding of Hunan Provincial Key Laboratory of Hepatobiliary Disease Research.

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  1. These authors contributed equally: Jie Fu, Guoxing Liu.

Authors and Affiliations

  1. Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, China

    Jie Fu, Xiao Zhang, Xiaohua Lei, Qiang Liu, Ke Qian, Qing Tong, Wei Qin, Zhenghao Li, Zhengyu Cao, Ju Zhang, Chun Liu, Zicheng Wang, Zhiqiang Liu & Xundi Xu

  2. Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China

    Guoxing Liu

  3. Wellman Center for Photomedicine, Division of Hematology and Oncology, Division of Endocrinology, Massachusetts General Hospital, VA Boston Healthcare System, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Xin M. Liang

  4. Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan

    Hirofumi Yamamoto

  5. Department of General Surgery, South China Hospital of Shenzhen University, Shenzhen, China

    Xundi Xu

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Contributions

JF, GL and XX conceived and designed the study. JF, GL, XL, QL, KQ, QT, WQ, ZL, ZC and JZ performed the experiments. CL, ZW and ZL contributed to sample collection. XL and HY contributed to picture arrangement. JF, GL, XZ and XX drafted the manuscript. All of the authors revised the manuscript.

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Correspondence to Xundi Xu.

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The authors declare no competing interests.

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All experiments performed in this study involving human samples were approved by the Clinical Research Ethics Committee of the Second Xiangya Hospital, Central South University. All patients have signed informed consent in accordance with the Declaration of Helsinki guidelines. All animal experiments were approved by the Animal Care and Use Committee of Central South University.

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Fu, J., Liu, G., Zhang, X. et al. TRPM8 promotes hepatocellular carcinoma progression by inducing SNORA55 mediated nuclear-mitochondrial communication. Cancer Gene Ther 30, 738–751 (2023). https://doi.org/10.1038/s41417-022-00583-x

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