Objective  To explore whether CYP2C9 is involved in the occurrence and development of hepatocellular carcinoma (HCC) and its function in the migration, invasion and proliferation of HCC cells.

Methods  The transcriptome data of HCC were retrieved from the TCGA database to analyze the expression of CYP2C9 and role of CYP2C9 in the prognosis of HCC; Constructing stable  CYP2C9 overexpression cell lines of HepG2 and MHCC97H, detecting the effects of CYP2C9 overexpression on the migration, invasion and epithelial mesenchymal transition (EMT) process of HCC cells through Transwell migration assay, Transwell invasion assay, and Western Blot assay, respectively; The effect of CYP2C9 overexpression on the proliferation ability of HCC cells was detected through CCK-8 assay, colony formation assay, and Western Blot assay.

Results  Bioinformatics analysis showed that the expression of CYP2C9 was significantly downregulated in HCC , and the expression of CYP2C9 was positively correlated with the clinical prognosis  of HCC patients; The results of cellular and molecular experiments showed that CYP2C9 overexpression significantly inhibited the migration, invasion and EMT process of HepG2 and MHCC97H cells, whereas had no significant effect on cell proliferation.

Conclusion  CYP2C9 may affect the progression of HCC by inhibiting the migration, invasion, and EMT processes of HCC cells.

1.Sung H, Ferlay J, Siegel RL, 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. DOI: 10.3322/caac.21660.

2.Villanueva A. Hepatocellular carcinoma[J]. N Engl J Med, 2019, 380(15): 1450-1462. DOI: 10.1056/NEJMra1713263.

3.Singal AG, Lampertico P, and Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: new trends[J]. J Hepatol, 2020, 72(2): 250-261. DOI: 10.1016/j.jhep.2019.08.025.

4.GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the global burden of disease study 2019[J]. Lancet, 2020, 396(10258): 1204-1222. DOI: 10.1016/S0140-6736(20)30925-9.

5.In der Stroth L, Tharehalli U, Günes C, et al. Telomeres and telomerase in the development of liver cancer[J]. Cancers (Basel), 2020, 12(8): 2048. DOI: 10.3390/cancers12082048.

6.Brar G, Greten TF, Graubard BI, et al. Hepatocellular carcinoma survival by etiology: a seer-medicare database analysis[J]. Hepatol Commun, 2020, 4(10): 1541-1551. DOI: 10.1002/hep4.1564.

7.Goutté N, Sogni P, Bendersky N, et al. Geographical variations in incidence, management and survival of hepatocellular carcinoma in a western country[J]. J Hepatol, 2017, 66(3): 537-544. DOI: 10.1016/j.jhep.2016.10.015.

8.Nebert DW, Russell DW. Clinical importance of the cytochromes p450[J]. Lancet, 2002, 360(9340): 1155-1162. DOI: 10.1016/S0140-6736(02)11203-7.

9.Zhao M, Ma J, Li M, et al. Cytochrome p450 enzymes and drug metabolism in humans[J]. Int J Mol Sci, 2021, 22(23): 12808. DOI: 10.3390/ijms222312808.

10.Guo Z, Johnson V, Barrera J, et al. Targeting cytochrome p450-dependent cancer cell mitochondria: cancer associated cyps and where to find them[J]. Cancer Metastasis Rev, 2018, 37(2-3): 409-423. DOI: 10.1007/s10555-018-9749-6.

11.Isvoran A, Louet M, Vladoiu D L, et al. Pharmacogenomics of the cytochrome p450 2c family: Impacts of amino acid variations on drug metabolism[J]. Drug Discov Today, 2017, 22(2): 366-376. DOI: 10.1016/j.drudis.2016.09.015.

12.Schmelzle M, Dizdar L, Matthaei H, et al. Esophageal cancer proliferation is mediated by cytochrome p450 2c9 (cyp2c9)[J]. Prostaglandins Other Lipid Mediat, 2011, 94(1-2): 25-33. DOI: 10.1016/j.prostaglandins. 2010.12.001.

13.Jiang Z, Zheng X, Wang W, et al. Cyp2c9 inhibits the invasion and migration of esophageal squamous cell carcinoma via downregulation of hdac[J]. Mol Cell Biochem, 2021, 476(5): 2011-2020. DOI: 10.1007/s11010-021-04050-3.

14.Shuaichen L, Guangyi W. Bioinformatic analysis reveals CYP2C9 as a potential prognostic marker for HCC and liver cancer cell lines suitable for its mechanism study[J]. Cell Mol Biol (Noisy-le-grand), 2018, 64(7): 70-74. https://pubmed.ncbi.nlm.nih.gov/29974848/.

15.Xu K, Xia P, Liu P, et al. A six lipid metabolism related gene signature for predicting the prognosis of hepatocellular carcinoma[J]. Sci Rep, 2022, 12(1): 20781. DOI: 10.1038/s41598-022-25356-2.

16.Campbell K and Casanova J. A common framework for EMT and collective cell migration[J]. Development, 2016, 143(23): 4291-4300. DOI: 10.1242/dev.139071.

17.Elisha Y, Kalchenko V, Kuznetsov Y, et al. Dual role of E-cadherin in the regulation of invasive collective migration of mammary carcinoma cells[J]. Sci Rep, 2018, 8(1): 4986. DOI: 10.1038/s41598-018-22940-3.

18.Chen Y, Rao X, Huang K, et al. FH535 inhibits proliferation and motility of colon cancer cells by targeting wnt/β-catenin signaling pathway[J]. J Cancer, 2017, 8(16): 3142-3153. DOI: 10.7150/jca.19273.

19.Huang Y, Hong W, and Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis[J]. J Hematol Oncol, 2022, 15(1): 129. DOI: 10.1186/s13045-022-01347-8.

20.Mittal V. Epithelial mesenchymal transition in tumor metastasis[J]. Annu Rev Pathol, 2018, 13: 395-412. DOI: 10.1146/annurev-pathol-020117-043854.

21.Xu Q, Liu X, Liu Z, et al. MicroRNA-1296 inhibits metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma by targeting SRPK1-mediated PI3K/AKT pathway[J]. Mol Cancer, 2017, 16(1): 103. DOI: 10.1186/s12943-017-0675-y.

22.Gao F, Xu T, Wang X, et al. CIP2A mediates fibronectin-induced bladder cancer cell proliferation by stabilizing β-catenin [J]. J Exp Clin Cancer Res, 2017, 36(1): 70. DOI: 10.1186/s13046-017-0539-8.

23.Tian W, Li J, Wang Z, et al. HYD-PEP06 suppresses hepatocellular carcinoma metastasis, epithelial-mesenchymal transition and cancer stem cell-like properties by inhibiting PI3K/AKT and WNT/β-catenin signaling activation[J]. Acta Pharm Sin B, 2021, 11(6): 1592-1606. DOI: 10.1016/j.apsb.2021.03.040.