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lncRNA miR4458HG modulates hepatocellular carcinoma progression by activating m6A-dependent glycolysis and promoting the polarization of tumor-associated macrophages

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Abstract

Long non-coding RNAs (lncRNAs) play significant roles in different biological functions of cancers. However, their function in the metabolism of glucose in patients with human hepatocellular carcinoma (HCC) remains largely unknown. In this study, HCC and paired intact liver tissues were utilized to examine the miR4458HG expression using qRT-PCR and human HCC cell lines to examine cell proliferation, colony formation, and glycolysis after transfection of siRNAs targeting miR4458HG or miR4458HG vectors. The molecular mechanism of miR4458HG was clarified through in situ hybridization, Western blotting, qRT-PCR, RNA pull-down, and RNA immunoprecipitation analysis. The results showed that the miR4458HG affected HCC cell proliferation, activated the glycolysis pathway, and promoted the polarization of tumor-associated macrophage in vitro and in vivo models. Mechanistically, miR4458HG bound IGF2BP2 (a key RNA m6A reader) and facilitated IGF2BP2-mediated target mRNA stability, including HK2 and SLC2A1 (GLUT1), and consequently altered HCC glycolysis and tumor cell physiology. At the same time, HCC-derived miR4458HG could be wrapped in the exosomes and promoted the polarization of tumor-associated macrophage by increasing ARG1 expression. Hence, miR4458HG is oncogenic in nature among patients with HCC. To develop an effective treatment strategy of HCC patients presenting with high glucose metabolism, physicians should focus on miR4458HG and its pathway.

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Data availability

The dataset generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by National Natural Science Foundation of China (81873178, 81904036), The leading talent Training Program of Pudong Health Burea of Shanghai (PWRl2019-03), Excellent subject leader training project of the three-year action plan of Shanghai public health system (GWV-10.2-XD15), and Key discipline construction project of the three-year action plan of Shanghai public health system (GWV-10.1-XK9).

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  1. Ying Ye and Menghan Wang Contributed equally.

Authors and Affiliations

  1. Central Laboratory, The Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China

    Ying Ye

  2. Department of Nuclear Medicine, The Seventh People’s Hospital, Shanghai University of Traditional Chinese Medicine, 358 Datong Rd, Pudong New Area, Shanghai, 200137, China

    Menghan Wang, Guoyu Wang, Zhongchao Mai, Borong Zhou, Yang Han, Juhua Zhuang & Wei Xia

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  1. Ying Ye
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Contributions

YY: conceptualization (equal); writing—original draft (equal). MW: investigation (equal); methodology (equal). GW: data curation (equal); software (equal). ZM: methodology (equal); validation (equal). BZ: investigation (equal); visualization (equal). YH: methodology (equal); data curation (equal); visualization (equal). JZ: software (equal); validation (equal). WX: conceptualization (equal); writing—review and editing (lead). All the authors read and approved the final manuscript.

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Correspondence to Wei Xia.

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No potential conflicts of interest were disclosed.

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Animal experiments were carried out in accordance with the standards approved by the Ethics Committee of The Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine.

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The use of samples from patients was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of The Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine. The need to obtain informed consent from the study patients was waived.

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Ye, Y., Wang, M., Wang, G. et al. lncRNA miR4458HG modulates hepatocellular carcinoma progression by activating m6A-dependent glycolysis and promoting the polarization of tumor-associated macrophages. Cell. Mol. Life Sci. 80, 99 (2023). https://doi.org/10.1007/s00018-023-04741-8

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  • DOI: https://doi.org/10.1007/s00018-023-04741-8

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