Abstract
Purpose
Suppressor of cytokine signaling-1 (SOCS-1) is a negative regulator of the Janus kinase/signal transducer and activation of transcription pathway. The purpose of this study was to investigate the relationship between methylation of SOCS-1 and sustained virologic response (SVR) in chronic hepatitis C (CHC) patients treated with pegylated interferon (PEG-IFN)-alpha and ribavirin (RBV).
Methods
In total, 106 CHC patients treated with PEG-IFN-alpha and RBV were included. Serum samples were obtained at baseline (P), end of treatment (EOT), and 6 months post treatment (F6). Methylation status of the promoter region of SOCS-1 was examined by quantitative methylation specific PCR (qMSP).
Results
Median baseline methylation level of SOCS-1 was −0.95 log10 copies/mL, which increased to 0.57 log10 copies/mL at EOT and then returned to −0.57 log10 copies/mL at F6 (baseline vs EOT, P < 0.001; EOT vs F6, P < 0.001). The overall SVR was 75.5 %. Univariate analysis indicated that SVR was significantly associated with genotype, baseline HCV RNA, body mass index (BMI) and higher EOT SOCS-1 methylation. Multivariate analysis confirmed that the SVR was significantly associated with genotype (OR: 13.40, 95 % CI: 1.73–103.58, P = 0.013), baseline HCV RNA (OR: 0.19, 95 % CI: 0.06–0.59, P = 0.004), BMI (OR: 0.73, 95 % CI: 0.56–0.96, P = 0.022), and EOT SOCS-1 methylation (OR: 1.71, 95 % CI: 1.11–2.62, P = 0.014).
Conclusion
CHC patients with significantly higher SOCS-1 methylation at the end of treatment had better SVRs. The role of SOCS-1 methylation in affecting treatment response deserves further investigation.
Similar content being viewed by others
Abbreviations
- HCV:
-
Hepatitis C virus
- CHC:
-
Chronic hepatitis C
- HCC:
-
Hepatocellular carcinoma
- PEG-IFN:
-
Pegylated interferon
- RBV:
-
Ribavirin
- SVR:
-
Sustained virologic response
- BMI:
-
Body mass index
- ALT:
-
Alanine aminotransferase
- SNPs:
-
Single nucleotide polymorphisms
- IL-28B:
-
Interleukin-28B
- SOCS:
-
Suppressors of cytokine signaling
References
Hoofnagle JH. Course and outcome of hepatitis C. Hepatology. 2002;36(5 Suppl 1):S21–9.
Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001;345(1):41–52.
Serfaty L, Aumaitre H, Chazouilleres O, et al. Determinants of outcome of compensated hepatitis C virus-related cirrhosis. Hepatology. 1998;27(5):1435–40.
Fattovich G, Stroffolini T, Zagni I, et al. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35–50.
Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463–72.
Chuang WL, Yu ML. Host factors determining the efficacy of hepatitis C treatment. J Gastroenterol. 2013;48(1):22–30.
Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(4):1433–44.
Rauch A, Kutalik Z, Descombes P, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology. 2010;138(4):1338–45.
Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41(10):1105–9.
Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41(10):1100–4.
Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007;7(6):454–65.
Bonjardim CA, Ferreira PC, Kroon EG. Interferons: signaling, antiviral and viral evasion. Immunol Lett. 2009;122(1):1–11.
Miyaaki H, Ichikawa T, Yatsuhashi H, et al. Suppressor of cytokine signal 3 and IL28 genetic variation predict the viral response to peginterferon and ribavirin. Hepatol Res. 2011;41(12):1216–22.
Miyaaki H, Ichikawa T, Nakao K, et al. Predictive value of suppressor of cytokine signal 3 (SOCS3) in the outcome of interferon therapy in chronic hepatitis C. Hepatol Res. 2009;39(9):850–5.
Persico M, Capasso M, Persico E, et al. Suppressor of cytokine signaling 3 (SOCS3) expression and hepatitis C virus-related chronic hepatitis: Insulin resistance and response to antiviral therapy. Hepatology. 2007;46(4):1009–15.
Walsh MJ, Jonsson JR, Richardson MM, et al. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut. 2006;55(4):529–35.
Imanaka K, Tamura S, Fukui K, et al. Enhanced expression of suppressor of cytokine signalling-1 in the liver of chronic hepatitis C: possible involvement in resistance to interferon therapy. J Viral Hepat. 2005;12(2):130–8.
Feinberg A. Cancer epigenetics takes center stage. Proc Natl Acad Sci USA. 2001;98:392–4.
Zhu J. DNA methylation and hepatocellular carcinoma. J Hepatobiliary Pancreat Surg. 2006;13(4):265–73.
To KF, Chan MW, Leung WK, et al. Constitutional activation of IL-6-mediated JAK/STAT pathway through hypermethylation of SOCS-1 in human gastric cancer cell line. Br J Cancer. 2004;91(7):1335–41.
Yoshikawa H, Matsubara K, Qian GS, et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet. 2001;28(1):29–35.
Miyoshi H, Fujie H, Moriya K, et al. Methylation status of suppressor of cytokine signaling-1 gene in hepatocellular carcinoma. J Gastroenterol. 2004;39(6):563–9.
Okochi O, Hibi K, Sakai M, et al. Methylation-mediated silencing of SOCS-1 gene in hepatocellular carcinoma derived from cirrhosis. Clin Cancer Res. 2003;9(14):5295–8.
Lee S, Lee HJ, Kim JH, et al. Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol. 2003;163(4):1371–8.
Fukai K, Yokosuka O, Imazeki F, et al. Methylation status of p14ARF, p15INK4b, and p16INK4a genes in human hepatocellular carcinoma. Liver Int. 2005;25(6):1209–16.
Su PF, Lee TC, Lin PJ, et al. Differential DNA methylation associated with hepatitis B virus infection in hepatocellular carcinoma. Int J Cancer. 2007;121(6):1257–64.
Tseng KC, Chang CK, Chou AL, et al. Prognostic effect of human leukocyte antigen class I and II alleles on chronic hepatitis C patients treated by pegylated interferon-alfa plus ribavirin in Taiwan. Hepatogastroenterology. 2010;57(99–100):456–61.
Ratge D, Scheiblhuber B, Nitsche M, et al. High-speed detection of blood-borne hepatitis C virus RNA by single-tube real-time fluorescence reverse transcription-PCR with the LightCycler. Clin Chem. 2000;46(12):1987–9.
Bullock GC, Bruns DE, Haverstick DM. Hepatitis C genotype determination by melting curve analysis with a single set of fluorescence resonance energy transfer probes. Clin Chem. 2002;48(12):2147–54.
Chan MW, Chu ES, To KF, et al. Quantitative detection of methylated SOCS-1, a tumor suppressor gene, by a modified protocol of quantitative real time methylation-specific PCR using SYBR green and its use in early gastric cancer detection. Biotechnol Lett. 2004;26(16):1289–93.
Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415–28.
Rodriguez-Paredes M, Esteller M. Cancer epigenetics reaches mainstream oncology. Nat Med. 2011;17(3):330–9.
Leung WK, To KF, Chu ES, et al. Potential diagnostic and prognostic values of detecting promoter hypermethylation in the serum of patients with gastric cancer. Br J Cancer. 2005;92(12):2190–4.
Jones PA. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat Rev Genet. 2012;13(7):484–92.
Zhang Q, Wang HY, Marzec M, et al. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc Natl Acad Sci U S A. 2005;102(19):6948–53.
Huang Y, Feld JJ, Sapp RK, et al. Defective hepatic response to interferon and activation of suppressor of cytokine signaling 3 in chronic hepatitis C. Gastroenterology. 2007;132(2):733–44.
MacQuillan GC, Mamotte C, Reed WD, et al. Upregulation of endogenous intrahepatic interferon stimulated genes during chronic hepatitis C virus infection. J Med Virol. 2003;70(2):219–27.
Song MM, Shuai K. The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities. J Biol Chem. 1998;273(52):35056–62.
Laird PW. The power and the promise of DNA methylation markers. Nat Rev Cancer. 2003;3(4):253–66.
Lee SD, Yu ML, Cheng PN, et al. Comparison of a 6-month course peginterferon alpha-2b plus ribavirin and interferon alpha-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan. J Viral Hepat. 2005;12(3):283–91.
Yu ML, Dai CY, Lee LP, et al. A 24-week course of high-dose interferon-alpha plus ribavirin for Taiwanese chronic hepatitis C patients with persistently normal or near-normal alanine aminotransferase levels. Liver Int. 2006;26(10):1187–95.
Acknowledgments
This study was supported by research grant from Dalin Tzu Chi Buddist Hospital (DTCRD97(2)-10), College of Science, National Chung Cheng University and National Science Council (NSC100-2320-B-194-002), Taiwan.
Disclosure
The authors declare no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Figure S1
Immunohistochemistry examination of SOCS-1 in liver biopsy from chronic hepatitis C patients. Sample with lower serum level of methylated SOCS-1 DNA (A1, 100×) have higher expression of SOCS-1 as shown by strong cytoplasmic staining; while sample with higher serum level of methylated SOCS-1 DNA (B1, 100×) have lower expression of SOCS-1. The high power images in the selected area are also shown (A2, B2, 400×). (PPT 627 kb)
Rights and permissions
About this article
Cite this article
Tseng, KC., Chou, JL., Huang, HB. et al. SOCS-1 Promoter Methylation and Treatment Response in Chronic Hepatitis C Patients Receiving Pegylated-Interferon/Ribavirin. J Clin Immunol 33, 1110–1116 (2013). https://doi.org/10.1007/s10875-013-9903-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-013-9903-4