Volume 22 Issue 10
Oct.  2024
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Article Navigation >  Chinese Journal of General Practice  > 2024  >  22(10): 1665-1670
YAN Junwei, ZHOU Lei, CHEN Shanshan, ZHANG Heng. MiR-375 Modulates HK2 via SP1 to Impact Proliferation and Glycolysis in Hepatocellular Carcinoma[J]. Chinese Journal of General Practice, 2024, 22(10): 1665-1670. doi: 10.16766/j.cnki.issn.1674-4152.003707
Citation: YAN Junwei, ZHOU Lei, CHEN Shanshan, ZHANG Heng. MiR-375 Modulates HK2 via SP1 to Impact Proliferation and Glycolysis in Hepatocellular Carcinoma[J]. Chinese Journal of General Practice, 2024, 22(10): 1665-1670. doi: 10.16766/j.cnki.issn.1674-4152.003707
shu

MiR-375 Modulates HK2 via SP1 to Impact Proliferation and Glycolysis in Hepatocellular Carcinoma

doi: 10.16766/j.cnki.issn.1674-4152.003707
  • 1.

    Department of Gastroenterology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, China

Funds:

 2023AFB458

 WX21Q45

  • Received Date: 2024-04-22
    Abstract
  •   Objective   To investigate the aberrant expression of hexokinase 2 (HK2) in hepatocellular carcinoma (HCC) and the regulatory mechanisms of cell proliferation and glycolysis in HCC.   Methods   A total of 41 cases of HCC and paracancerous tissues that underwent surgical resection at the Central Hospital of Wuhan between January 2017 and December 2019 were collected for pathological examination. The expression of HK2 and SP1 was evaluated through immunohistochemical staining. In the HepG2 cell line, HK2 and SP1 were knocked down, and miR-375 was overexpressed. The assessment of cell proliferation and glycolytic capacity was conducted through the utilization of CCK-8, glucose, and lactate concentration assays. The regulatory relationships among HK2, SP1, and miR-375 were validated through the implementation of real-time quantitative PCR (RT-qPCR) and Western blotting techniques. The correlation among these factors was analyzed through the utilization of the gene expression omnibus (GEO) HCC dataset. The direct interaction between miR-375 and SP1 was confirmed through the utilization of a luciferase reporter assay.   Results   IHC revealed that the high expression rates of SP1 and HK2 in paracancerous tissues were 39.0% (16/41) and 26.8% (11/41), respectively. In HCC tissues, these rates increased to 58.5% (24/41) and 53.7% (22/41) respectively. A positive correlation was observed between SP1 and HK2 expression scores (r=0.611, P < 0.001). The downregulation of HK2 and SP1, and the upregulation of miR-375, resulted in the inhibition of HCC cell proliferation and glycolysis. The upregulation of miR-375 and downregulation of SP1 resulted in the suppression of HK2 expression. Bioinformatics analysis revealed a negative correlation between HK2 and miR-375 expression (r=-0.584, P < 0.001) and a positive correlation between HK2 and SP1 expression (r=0.297, P=0.005). Additionally, miR-375 was identified as a direct target of SP1, exhibiting inhibitory effects at both mRNA and protein levels. The luciferase reporter assay provided confirmation of the direct interaction between miR-375 and SP1.   Conclusion   The miR-375 has been demonstrated to regulate HK2 by targeting the transcription factor SP1, thereby influencing the proliferation and glycolysis of HCC.

     

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  • [1]
    VOGEL A, MEYER T, SAPISOCHIN G, et al. Hepatocellular carcinoma[J]. Lancet, 2022, 400(10360): 1345-1362. doi: 10.1016/S0140-6736(22)01200-4
    [2]
    刘威, 张逸寅, 赵芳, 等. PD-1抑制剂联合抗血管生成药物治疗晚期肝细胞癌的疗效及预后影响因素分析[J]. 中华全科医学, 2024, 22(1): 64-69. doi: 10.16766/j.cnki.issn.1674-4152.003332

    LIU W, ZHANG YY, ZHAO F, et al. Analysis of the efficacy and prognostic factors influencing the treatment of advanced hepatocellular carcinoma with PD-1 inhibitors combined with antiangiogenic drugs[J]. Chinese Journal of General Practice, 2024, 22(1): 64-69. doi: 10.16766/j.cnki.issn.1674-4152.003332
    [3]
    曾珠, 廖正银. 晚期肝细胞肝癌治疗中免疫检查点抑制剂的应用[J]. 华西医学, 2020, 35(2): 230-235.

    ZENG Z, LIAO Z Y. Application of immune checkpoint inhibitors in the treatment of advanced hepatocellular carcinoma[J]. West China Medicine, 2020, 35(2): 230-235.
    [4]
    DU D, LIU C, QIN M, et al. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma[J]. Acta Pharm Sin B, 2022, 12(2): 558-580. doi: 10.1016/j.apsb.2021.09.019
    [5]
    耿西林, 张颖, 李浩, 等. 线粒体动力相关蛋白DRP1对肝癌细胞糖代谢的调控作用研究[J]. 中华全科医学, 2022, 20(1): 35-38. doi: 10.16766/j.cnki.issn.1674-4152.002270

    GENG X L, ZHANG Y, LI H, et al. Regulation of glucose metabolism in hepatocellular carcinoma cells by mitochondrial power-related protein DRP1[J]. Chinese Journal of General Practice, 2022, 20(1): 35-38. doi: 10.16766/j.cnki.issn.1674-4152.002270
    [6]
    ALVES A P, MAMEDE A C, ALVES M G, et al. Glycolysis inhibition as a strategy for hepatocellular carcinoma treatment?[J]. Curr Cancer Drug Targets, 2019, 19(1): 26-40.
    [7]
    DEWAAL D, NOGUEIRA V, TERRY A R, et al. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin[J]. Nat Commun, 2018, 9(1): 446. doi: 10.1038/s41467-017-02733-4
    [8]
    FENG J, LI J, WU L, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma[J]. J Exp Clin Cancer Res, 2020, 39(1): 126. doi: 10.1186/s13046-020-01629-4
    [9]
    GARCIA S N, GUEDES R C, MARQUES M M. Unlocking the potential of HK2 in cancer metabolism and therapeutics[J]. Curr Med Chem, 2019, 26(41): 7285-7322.
    [10]
    CISCATO F, FERRONE L, MASGRAS I, et al. Hexokinase 2 in cancer: a prima donna playing multiple characters[J]. Int J Mol Sci, 2021, 22(9): 4716. DOI: 10.3390/ijms22094716.
    [11]
    DU D, LIU C, QIN M, et al. Metabolic dysregulation and emerging therapeutical targets for hepatocellular carcinoma[J]. Acta Pharmaceutica Sinica B, 2022, 12(2): 558-580. doi: 10.1016/j.apsb.2021.09.019
    [12]
    WATZKY M, HUARD S, JURICEK L, et al. Hexokinase 2 is a transcriptional target and a positive modulator of AHR signalling[J]. Nucleic Acids Res, 2022, 50(10): 5545-5564. doi: 10.1093/nar/gkac360
    [13]
    DOU C, MO H, CHEN T, et al. ZMYND8 promotes the growth and metastasis of hepatocellular carcinoma by promoting HK2-mediated glycolysis[J]. Pathol Res Pract, 2021, 219: 153345. DOI: 10.1016/j.prp.2021.153345.
    [14]
    JIN F, WANG Y, ZHU Y, et al. The miR-125a/HK2 axis regulates cancer cell energy metabolism reprogramming in hepatocellular carcinoma[J]. Sci Rep, 2017, 7(1): 3089. doi: 10.1038/s41598-017-03407-3
    [15]
    XU F, YAN J J, GAN Y, et al. miR-885-5p negatively regulates warburg effect by silencing hexokinase 2 in liver cancer[J]. Mol Ther Nucleic Acids, 2019, 18: 308-319. doi: 10.1016/j.omtn.2019.09.002
    [16]
    WANG J, CHEN J, SUN F, et al. miR-202 functions as a tumor suppressor in hepatocellular carcinoma by targeting HK2[J]. Oncol Lett, 2020, 19(3): 2265-2271.
    [17]
    GUO W, QIU Z, WANG Z, et al. MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer[J]. Hepatology (Baltimore, Md), 2015, 62(4): 1132-1144. doi: 10.1002/hep.27929
    [18]
    王迪迪, 黄玉荣, 王建君, 等. miR-148b-3p通过调节脂代谢基因对肝癌细胞恶性生物学行为的影响[J]. 贵州医科大学学报, 2023, 48(10): 1129-1136, 1144.

    WANG D D, HUANG Y R, WANG J J, et al. Effect of miR-148b-3p on the malignant biological behaviors of hepatocellular carcinoma cells by regulating lipid metabolism genes[J]. Journal of Guizhou Medical University, 2023, 48(10): 1129-1136, 1144.
    [19]
    SAFE S. Specificity proteins (Sp) and cancer[J]. Int J Mol Sci, 2023, 24(6): 5164. DOI: 10.3390/ijms24065164.
    [20]
    WEI J, LU Y, WANG R, et al. MicroRNA-375: potential cancer suppressor and therapeutic drug[J]. Biosci Rep, 2021, 41(9): BSR20211494. DOI: 10.1042/BSR20211494.
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