Sofosbuvir Induces Gene Expression for Promoting Cell Proliferation and Migration of Hepatocellular Carcinoma Cells

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2022 Jul 14

PMID 35833210

Authors

Wei-Lun Tsai

Jin-Shiung Cheng

Pei-Feng Liu

Tsung-Hsien Chang

Wei-Chih Sun

Wen-Chi Chen

Chih-Wen Shu

Affiliations

Soon will be listed here.

Abstract

Direct-acting antivirals (DAAs) have achieved a sustained virological response (SVR) rate of 95-99% in treating HCV. Several studies suggested that treatment with sofosbuvir (SOF), one type of DAAs, may be associated with increased risk of developing HCC. The aim of this study is to investigate the potential mechanisms of SOF on the development of HCC. OR-6 (harboring full-length genotype 1b HCV) and Huh 7.5.1 cells were used to examine the effects of SOF on cell proliferation and migration of HCC cells. SOF-upregulated genes in OR-6 cells were inspected using next generation sequencing (NGS)and the clinical significance of these candidate genes was analyzed using The Cancer Genome Atlas (TCGA) database. We found that SOF increased cell proliferation and cell migration in OR-6 and Huh 7.5.1 cells. Several SOF-upregulated genes screened from NGS were confirmed by real-time PCR in OR-6 cells. Among these genes, PHOSPHO2, KLHL23, TRIM39, TSNAX-DISC1 and RPP21 expression were significantly elevated in the tumor tissues compared with the non-tumor tissues of HCC according to TCGA database. High expression of PHOSPHO2 and RPP21 was associated with poor overall survival of HCC patients. Moreover, knockdown of PHOSPHO2-KLHL23, TSNAX-DISC1, TRIM39 and RPP21 diminished cell proliferation and migration increased by SOF in OR-6 and Huh 7.5.1 cells. In conclusion, SOF-upregulated genes promoted HCC cell proliferation and migration, which might be associated with the development of HCC.

Citing Articles

Comprehensive Analysis of METTLs (METTL1/13/18/21A/23/25/2A/2B/5/6/9) and Associated mRNA Risk Signature in Hepatocellular Carcinoma.

Wang H, Hu S, Nie J, Qin X, Zhang X, Wang Q Anal Cell Pathol (Amst). 2023; 2023:6007431.

PMID: 38130905 PMC: 10735724. DOI: 10.1155/2023/6007431.

References

Schaefer E, Chung R . Anti-hepatitis C virus drugs in development. Gastroenterology. 2012; 142(6):1340-1350.e1. DOI: 10.1053/j.gastro.2012.02.015. View

. Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts. J Hepatol. 2016; 65(4):734-740. DOI: 10.1016/j.jhep.2016.05.045. View

Vermehren J, Park J, Jacobson I, Zeuzem S . Challenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection. J Hepatol. 2018; 69(5):1178-1187. DOI: 10.1016/j.jhep.2018.07.002. View

Sarin S, Kumar M, Eslam M, George J, Al Mahtab M, Akbar S . Liver diseases in the Asia-Pacific region: a Lancet Gastroenterology & Hepatology Commission. Lancet Gastroenterol Hepatol. 2019; 5(2):167-228. PMC: 7164809. DOI: 10.1016/S2468-1253(19)30342-5. View

Ogawa E, Nomura H, Nakamuta M, Furusyo N, Kajiwara E, Dohmen K . Incidence of Hepatocellular Carcinoma after Treatment with Sofosbuvir-Based or Sofosbuvir-Free Regimens in Patients with Chronic Hepatitis C. Cancers (Basel). 2020; 12(9). PMC: 7563479. DOI: 10.3390/cancers12092602. View

Tao H, Li Z, Mei Y, Li X, Lou H, Dong L . Integrative bioinformatics analysis of a prognostic index and immunotherapeutic targets in renal cell carcinoma. Int Immunopharmacol. 2020; 87:106832. DOI: 10.1016/j.intimp.2020.106832. View

Fortner R, Damms-Machado A, Kaaks R . Systematic review: Tumor-associated antigen autoantibodies and ovarian cancer early detection. Gynecol Oncol. 2017; 147(2):465-480. DOI: 10.1016/j.ygyno.2017.07.138. View

Liu Z, Lin Y, Gao X, Mai R, Piao X, Ye J . Construction of a Comprehensive Multiomics Map of Hepatocellular Carcinoma and Screening of Possible Driver Genes. Front Genet. 2020; 11:634. PMC: 7330124. DOI: 10.3389/fgene.2020.00634. View

Matsushita J, Suzuki T, Okamura K, Ichihara G, Nohara K . Identification by TCGA database search of five genes that are aberrantly expressed and involved in hepatocellular carcinoma potentially via DNA methylation changes. Environ Health Prev Med. 2020; 25(1):31. PMC: 7376645. DOI: 10.1186/s12199-020-00871-8. View

10.

Ono A, Goossens N, Finn R, Schmidt W, Thung S, Im G . Persisting risk of hepatocellular carcinoma after hepatitis C virus cure monitored by a liver transcriptome signature. Hepatology. 2017; 66(4):1344-1346. PMC: 5605396. DOI: 10.1002/hep.29203. View

11.

Sultan M, Schulz M, Richard H, Magen A, Klingenhoff A, Scherf M . A global view of gene activity and alternative splicing by deep sequencing of the human transcriptome. Science. 2008; 321(5891):956-60. DOI: 10.1126/science.1160342. View

12.

. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol. 2018; 69(2):461-511. DOI: 10.1016/j.jhep.2018.03.026. View

13.

Li D, Ren Y, Fierer D, Rutledge S, Shaikh O, Lo Re 3rd V . The short-term incidence of hepatocellular carcinoma is not increased after hepatitis C treatment with direct-acting antivirals: An ERCHIVES study. Hepatology. 2017; 67(6):2244-2253. DOI: 10.1002/hep.29707. View

14.

Zhang L, Mei Y, Fu N, Guan L, Xie W, Liu H . TRIM39 regulates cell cycle progression and DNA damage responses via stabilizing p21. Proc Natl Acad Sci U S A. 2012; 109(51):20937-42. PMC: 3529087. DOI: 10.1073/pnas.1214156110. View

15.

Shiha G, Mousa N, Soliman R, Nnh Mikhail N, Adel Elbasiony M, Khattab M . Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: A prospective study. J Viral Hepat. 2020; 27(7):671-679. DOI: 10.1111/jvh.13276. View

16.

Suzuki T, Ishii K, Aizaki H, Wakita T . Hepatitis C viral life cycle. Adv Drug Deliv Rev. 2007; 59(12):1200-12. DOI: 10.1016/j.addr.2007.04.014. View

17.

Ikeda M, Abe K, Dansako H, Nakamura T, Naka K, Kato N . Efficient replication of a full-length hepatitis C virus genome, strain O, in cell culture, and development of a luciferase reporter system. Biochem Biophys Res Commun. 2005; 329(4):1350-9. DOI: 10.1016/j.bbrc.2005.02.138. View

18.

Pearlman B, Hinds A . Review article: novel antivirals for hepatitis C-sofosbuvir/velpatasvir/voxilaprevir, glecaprevir/pibrentasvir. Aliment Pharmacol Ther. 2018; 48(9):914-923. DOI: 10.1111/apt.14977. View

19.

Villani R, Facciorusso A, Bellanti F, Tamborra R, Piscazzi A, Landriscina M . DAAs Rapidly Reduce Inflammation but Increase Serum VEGF Level: A Rationale for Tumor Risk during Anti-HCV Treatment. PLoS One. 2016; 11(12):e0167934. PMC: 5172554. DOI: 10.1371/journal.pone.0167934. View

20.

Li N, Zheng J, Li H, Deng J, Hu M, Wu H . Identification of chimeric TSNAX-DISC1 resulting from intergenic splicing in endometrial carcinoma through high-throughput RNA sequencing. Carcinogenesis. 2014; 35(12):2687-97. DOI: 10.1093/carcin/bgu201. View