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. 2024 Jul 5:974:176601.
doi: 10.1016/j.ejphar.2024.176601. Epub 2024 Apr 25.

Hypoxia-induced TRPM7 promotes glycolytic metabolism and progression in hepatocellular carcinoma

Fengbo Zhao  1 , Weili Yu  1 , Jingyan Hu  1 , Yi Xia  1 , YuXuan Li  1 , Siqi Liu  1 , Aifen Liu  1 , Chengniu Wang  1 , Hong Zhang  2 , Lei Zhang  3 , Jianwu Shi  4
Affiliations

Hypoxia-induced TRPM7 promotes glycolytic metabolism and progression in hepatocellular carcinoma

Fengbo Zhao et al. Eur J Pharmacol. .

Abstract

Background: Hypoxia disrupts glucose metabolism in hepatocellular carcinoma (HCC). Transient receptor potential cation channel, subfamily M, member 7 (TRPM7) plays an ontogenetic role. Thus, we aimed to explore the regulation of TRPM7 by hypoxia-induced factor (HIF) and its underlying mechanisms in HCC.

Methods: hypoxia was induced in multiple HCC cells using 1% O2 or CoCl2 treatment, and subsequently blocked using siRNAs targeting HIF-1α or HIF-2α as well as a HIF-1α protein synthesis inhibitor. The levels of HIF-1α and TRPM7 were assessed using quantitative PCR (qPCR) and Western blot analysis. Chromatin immunoprecipitation (ChIP) and luciferase assays were performed to observe the regulation of TRPM7 promoter regions by HIF-1α. A PCR array was utilized to screen glucose metabolism-related enzymes in HEK293 cells overexpressing TRPM7 induced by tetracycline, and then verified in TRPM7-overexpressed huh7 cells. Finally, CCK-8, transwell, scratch and tumor formation experiments in nude mice were conducted to examine the effect of TRPM7 on proliferation and metastasis in HCC.

Results: Exposure to hypoxia led to increase the levels of TRPM7 and HIF-1α in HCC cells, which were inhibited by HIF-1α siRNA or enhanced by HIF-1α overexpression. HIF-1α directly bound to two hypoxia response elements (HREs) in the TRPM7 promoter. Several glycolytic metabolism-related enzymes, were simultaneously upregulated in HEK293 and huh7 cells overexpressing TRPM7 during hypoxia. In vitro and in vivo experiments demonstrated that TRPM7 promoted the proliferation and metastasis of HCC cells.

Conclusions: TRPM7 was directly transcriptionally regulated by HIF-1α, leading to glycolytic metabolic reprogramming and the promotion of HCC proliferation and metastasis in vitro and in vivo. Our findings suggest that TRPM7 might be a potential diagnostic indicator and therapeutic target for HCC.

Keywords: Glycolysis; HIF-1α; Hepatocellular carcinoma; Hypoxia; TRPM7.

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Conflict of interest statement

Declaration of competing interest The authors declare no conflict of interest. I declare that this manuscript entitled “Hypoxia-induced TRPM7 Promotes Glycolytic Metabolism and Progression in Hepatocellular Carcinoma” is original, has not been published before and is not currently being considered for publication elsewhere. I would like to draw the attention of the Editor to the following publications of one or more of us that refer to aspects of the manuscript presently being submitted. Where relevant copies of such publications are attached. I confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. I further confirm that the order of authors listed in the manuscript has been approved by all of us. I understand that the Corresponding Author is the sole contact for the Editorial process. He/she is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.

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