The effect of GINS1 on glycolysis, epithelial-mesenchymal transition and angiogenesis in hepatocellular carcinoma

Abstract

Abstract: Objective To investigate the effects of GINS1 on glycolysis, epithelial-mesenchymal transition (EMT), and angiogenesis in hepatocellular carcinoma (HCC). Methods GINS1 knockdown was performed in HCC cell lines MHCC97H and Hep3B cells (shGINS1-NC, shGINS1), and the expression levels of glycolysis-related proteins and EMT-related proteins were detected by Western blot. Cell proliferation activity was detected by EDU assay and colony formation assay, and cell metastasis activity was detected by scratch assay and Transwell assay. HUVEC cells were co-cultured to detect tumor angiogenesis ability. Twelve nude mice HCC xenograft models were constructed and divided into shGINS1-NC-nude and shGINS1-nude groups, with 6 mice in each group. The tumor volume of the two groups of nude mice were observed, and the expression level of glycolysis-related proteins and EMT-related proteins were detected. Results Compared with the shGINS1-NC group, the protein levels of GLUT1, HK2, LDHA, Vimentin, and N-cadherin were decreased, and the protein levels of E-cadherin and ZO-1 were increased in the shGINS1 group, and the cell proliferation, metastasis, and angiogenesis abilities were significantly inhibited (all P<0.05). Compared with the shGINS1-NC-nude group, the tumor volume and weight were reduced, and the protein levels of GLUT1, HK2, LDHA, Vimentin, and N-cadherin were decreased, and the protein levels of E-cadherin and ZO-1 were increased in the shGINS1-nude group (all P<0.05). Conclusion Downregulation of GINS1 expression level can inhibit HCC cell glycolysis, EMT, angiogenesis and metastasis.

Key words: GINS1, Hepatocellular carcinoma, Glycolysis, Epithelial-mesenchymal transition, Angiogenesis

LV Yu-qing, CHEN Si. The effect of GINS1 on glycolysis, epithelial-mesenchymal transition and angiogenesis in hepatocellular carcinoma[J]. Chinese Hepatolgy, 2026, 31(4): 539-544.

References

[1] Rumgay H, Arnold M, Ferlay J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040[J]. J Hepatol, 2022, 77(6):1598-1606.
[2] Chidambaranathan-Reghupaty S, Fisher P B, Sarkar D. Hepatocellular carcinoma (HCC): epidemiology, etiology and molecular classification[J]. Adv Cancer Res, 2021, 149:1-61.
[3] Coffin P, He A. Hepatocellular carcinoma: past and present challenges and progress in molecular classification and precision oncology[J]. Int J Mol Sci, 2023, 24(17):13274.
[4] Chan Y T, Zhang C, Wu J, et al. Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma[J]. Mol Cancer, 2024, 23(1):189.
[5] Bracken C P, Goodall G J. The many regulators of epithelial-mesenchymal transition[J]. Nat Rev Mol Cell Biol, 2022, 23(2):89-90.
[6] Chen D, Aierken A, Li H, et al. Identification of subclusters and prognostic genes based on glycolysis/gluconeogenesis in hepatocellular carcinoma[J]. Front Immunol, 2023, 14:1232390.
[7] Fu Q, Zheng H, Wang X, et al. GINS1 promotes the initiation and progression of bladder cancer by activating the AKT/mTOR/c-Myc signaling pathway[J]. Exp Cell Res, 2024, 440(1):114125.
[8] Ge R, Wang C, Liu J, et al. A novel tumor-promoting role for nuclear factor Ⅸ in glioblastoma is mediated through transcriptional activation of GINS1[J]. Mol Cancer Res, 2023, 21(3):189-198.
[9] 霍怡杉,徐晓慧,马秀敏,等. GINS1通过激活Notch/PI3K/AKT/mTORC1信号通路增强肺腺癌细胞糖酵解、增殖和转移[J].中国肺癌杂志,2024,27(10):735-744.
[10] Liang J, Yao N, Deng B, et al. GINS1 promotes ZEB1-mediated epithelial-mesenchymal transition and tumor metastasis via β-catenin signaling in hepatocellular carcinoma[J]. J Cell Physiol, 2024, 239(5):e31237.
[11] 寻琛,秦叔逵.肝细胞癌辅助治疗研究进展和挑战[J].临床肿瘤学杂志,2024,29(9):904-913.
[12] 高小青,姜胜攀,李军,等.肝细胞癌切除术后早期复发和转移的危险因素分析及Nomogram模型构建[J].国际消化病杂志,2023,43(5):339-347.
[13] Zhang Y, Li W, Bian Y, et al. Multifaceted roles of aerobic glycolysis and oxidative phosphorylation in hepatocellular carcinoma[J]. PeerJ, 2023, 11:e14797.
[14] Xu S, Herschman H R. A tumor agnostic therapeutic strategy for hexokinase 1-null/hexokinase 2-positive cancers[J]. Cancer Res, 2019, 79(23):5907-5914.
[15] Ganapathy-Kanniappan S. Molecular intricacies of aerobic glycolysis in cancer: current insights into the classic metabolic phenotype[J]. Crit Rev Biochem Mol Biol, 2018, 53(6):667-682.
[16] 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.
[17] Dai Y W, Chen H B, Pan Y T, et al. Characterization of chromatin regulators identified prognosis and heterogeneity in hepatocellular carcinoma[J]. Front Oncol, 2022, 12:1002781.
[18] Li H, Song J, He Y, et al. CRISPR/Cas9 screens reveal that hexokinase 2 enhances cancer stemness and tumorigenicity by activating the ACSL4-fatty acid β-oxidation pathway[J]. Adv Sci (Weinh), 2022, 9(21):e2105126.
[19] 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.
[20] Sun R F, Zhao C Y, Chen S, et al. Androgen receptor stimulates hexokinase 2 and induces glycolysis by PKA/CREB signaling in hepatocellular carcinoma[J]. Dig Dis Sci, 2021, 66(3):802-813.
[21] Sung H, Ferlay J, Siegel R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3):209-249.
[22] Jinesh G G, Brohl A S. Classical epithelial-mesenchymal transition (EMT) and alternative cell death process-driven blebbishield metastatic-witch (BMW) pathways to cancer metastasis[J]. Signal Transduct Target Ther, 2022, 7(1):296.
[23] Liu Z L, Chen H H, Zheng L L, et al. Angiogenic signaling pathways and anti-angiogenic therapy for cancer[J]. Signal Transduct Target Ther, 2023, 8(1):198.
[24] Ansari M J, Bokov D, Markov A, et al. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review[J]. Cell Commun Signal, 2022, 20(1):49.