Skip to main content
SpringerLink
Log in

Reduced expression of SOCS2 and SOCS6 in hepatocellular carcinoma correlates with aggressive tumor progression and poor prognosis

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

To investigate the clinical significance of suppressor of cytokine signaling (SOCS)-2 and SOCS6 in human hepatocellular carcinoma (HCC). The expression levels of SOCS2 and SOCS6 mRNA and protein in tumor, para-tumor and normal liver tissues were detected in 106 HCC patients by real-time quantitative RT-PCR (qRT-PCR) and Western blot. According to qRT-PCR and western blot analyses, we first found that both the expression levels of SOCS2 and SOCS6 mRNA and protein in HCC were significantly lower than those in para-tumor (both P < 0.001) and normal liver tissues (both P < 0.001). Then, the correlation analysis showed that both SOCS2 and SOCS6 protein downregulation were significantly correlated with advanced TNM stage (both P < 0.001) and high serum AFP (P = 0.008 and 0.01, respectively). Especially, the reduced expression of SOCS2 more frequently occurred in HCC patients with vascular invasion (P = 0.03), and that of SOCS6 was also associated with tumor recurrence (P = 0.01). Moreover, HCC patients with low expression of SOCS2 and SOCS6 had significantly shorter overall (P = 0.008 and 0.01, respectively) and disease-free survival (both P = 0.01). Furthermore, multivariate analysis showed that both SOCS2 and SOCS6 downregulation were independent prognostic factors of overall (P = 0.01 and 0.03, respectively) and disease-free survival (P = 0.01 and 0.03, respectively) in HCC. Our data demonstrate for the first time that SOCS2 and SOCS6 expression were remarkably reduced in HCC and may be served as potential prognostic markers for patients with this deadly disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics. CA Cancer J Clin 55:74–108

    Article  PubMed  Google Scholar 

  2. Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42:1208–1236

    Article  PubMed  Google Scholar 

  3. El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576

    Article  PubMed  CAS  Google Scholar 

  4. Fujimoto M, Naka T (2003) Regulation of cytokine signaling by SOCS family molecules. Trends Immunol 24:659–666

    Article  PubMed  CAS  Google Scholar 

  5. Kile BT, Schulman BA, Alexander WS, Nicola NA, Martin HM, Hilton DJ (2002) The SOCS box: a tale of destruction and degradation. Trends Biochem Sci 27:235–241

    Article  PubMed  CAS  Google Scholar 

  6. Elliott J, Johnston JA (2004) SOCS: role in inflammation, allergy and homeostasis. Trends Immunol 25:434–440

    Article  PubMed  CAS  Google Scholar 

  7. Okochi O, Hibi K, Sakai M, Inoue S, Takeda S, Kaneko T, Nakao A (2003) Methylation-mediated silencing of SOCS-1 gene in hepatocellular carcinoma derived from cirrhosis. Clin Cancer Res 9:5295–5298

    PubMed  CAS  Google Scholar 

  8. Niwa Y, Kanda H, Shikauchi Y, Saiura A, Matsubara K, Kitagawa T, Yamamoto J, Kubo T, Yoshikawa H (2005) Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 24:6406–6417

    PubMed  CAS  Google Scholar 

  9. Rico-Bautista E, Flores-Morales A, Fernández-Pérez L (2006) Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Cytokine Growth Factor Rev 17:431–439

    Article  PubMed  CAS  Google Scholar 

  10. Tannahill GM, Elliott J, Barry AC, Hibbert L, Cacalano NA, Johnston JA (2005) SOCS2 can enhance interleukin-2 (IL-2) and IL-3 signaling by accelerating SOCS3 degradation. Mol Cell Biol 25:9115–9126

    Article  PubMed  CAS  Google Scholar 

  11. Jegalian AG, Wu H (2002) Differential roles of SOCS family members in EpoR signal transduction. J Interferon Cytokine Res 22:853–860

    Article  PubMed  CAS  Google Scholar 

  12. Goldshmit Y, Walters CE, Scott HJ, Greenhalgh CJ, Turnley AM (2004) SOCS2 induces neurite outgrowth by regulation of epidermal growth factor receptor activation. J Biol Chem 279:16349–16355

    Article  PubMed  CAS  Google Scholar 

  13. Schultheis B, Carapeti-Marootian M, Hochhaus A, Weisser A, Goldman JM, Melo JV (2002) Overexpression of SOCS-2 in advanced stages of chronic myeloid leukemia: possible inadequacy of a negative feedback mechanism. Blood 99:1766–1775

    Article  PubMed  CAS  Google Scholar 

  14. Wikman H, Kettunen E, Seppanen JK, Karjalainen A, Hollmen J, Anttila S et al (2002) Identification of differentially expressed genes in pulmonary adenocarcinoma by using cDNA array. Oncogene 21:5804–5813

    Article  PubMed  CAS  Google Scholar 

  15. Sutherland KD, Lindeman GJ, Choong DY, Wittlin S, Brentzell L, Phillips W et al (2004) Differential hypermethylation of SOCS genes in ovarian and breast carcinomas. Oncogene 23:7726–7733

    Article  PubMed  CAS  Google Scholar 

  16. Arany I, Muldrow M, Tyring SK (2001) The endogenous interferon system in anal squamous epithelial lesions with different grades from HIV-positive individuals. Int J STD AIDS 12:229–233

    Article  PubMed  CAS  Google Scholar 

  17. Hwang MN, Min CH, Kim HS, Lee H, Yoon KA, Park SY, Lee ES, Yoon S (2007) The nuclear localization of SOCS6 requires the N-terminal region and negatively regulates Stat3 protein levels. Biochem Biophys Res Commun 360:333–338

    Article  PubMed  CAS  Google Scholar 

  18. Wang T, Gao Q, Nie P, Secombes CJ (2010) Identification of suppressor of cytokine signalling (SOCS) 6, 7, 9 and CISH in rainbow trout Oncorhynchus mykiss and analysis of their expression in relation to other known trout SOCS. Fish Shellfish Immunol 29:656–667

    Article  PubMed  CAS  Google Scholar 

  19. Lin HY, Lai RH, Lin ST, Lin RC, Wang MJ, Lin CC, Lee HC, Wang FF, Chen JY (2013) Suppressor of cytokine signaling 6 (SOCS6) promotes mitochondrial fission via regulating DRP1 translocation. Cell Death Differ 20:139–153

    Article  PubMed  CAS  Google Scholar 

  20. Sriram KB, Larsen JE, Savarimuthu Francis SM, Wright CM, Clarke BE, Duhig EE, Brown KM, Hayward NK, Yang IA, Bowman RV, Fong KM (2012) Array-comparative genomic hybridization reveals loss of SOCS6 is associated with poor prognosis in primary lung squamous cell carcinoma. PLoS ONE 7:e30398

    Article  PubMed  CAS  Google Scholar 

  21. Storojeva I, Boulay JL, Ballabeni P, Buess M, Terracciano L, Laffer U, Mild G, Herrmann R, Rochlitz C (2005) Prognostic and predictive relevance of DNAM-1, SOCS6 and CADH-7 genes on chromosome 18q in colorectal cancer. Oncology 68:246–255

    Article  PubMed  CAS  Google Scholar 

  22. Lai RH, Hsiao YW, Wang MJ, Lin HY, Wu CW, Chi CW, Li AF, Jou YS, Chen JY (2010) SOCS6, down-regulated in gastric cancer, inhibits cell proliferation and colony formation. Cancer Lett 288:75–85

    Article  PubMed  CAS  Google Scholar 

  23. Yoon S, Yi YS, Kim SS, Kim JH, Park WS, Nam SW (2012) SOCS5 and SOCS6 have similar expression patterns in normal and cancer tissues. Tumour Biol 33:215–221

    Article  PubMed  CAS  Google Scholar 

  24. Farabegoli F, Ceccarelli C, Santini D, Taffurelli M (2005) Suppressor of cytokine signalling 2 (SOCS-2) expression in breast carcinoma. J Clin Pathol 58:1046–1050

    Article  PubMed  CAS  Google Scholar 

  25. Haffner MC, Petridou B, Peyrat JP, Révillion F, Müller-Holzner E, Daxenbichler G, Marth C, Doppler W (2007) Favorable prognostic value of SOCS2 and IGF-I in breast cancer. BMC Cancer 7:136

    Article  PubMed  Google Scholar 

  26. Hendriksen PJ, Dits NF, Kokame K, Veldhoven A, van Weerden WM, Bangma CH, Trapman J, Jenster G (2006) Evolution of the androgen receptor pathway during progression of prostate cancer. Cancer Res 66:5012–5020

    Article  PubMed  CAS  Google Scholar 

  27. Raccurt M, Tam SP, Lau P, Mertani HC, Lambert A, Garcia-Caballero T, Li H, Brown RJ, McGuckin MA, Morel G, Waters MJ (2003) Suppressor of cytokine signalling gene expression is elevated in breast carcinoma. Br J Cancer 89:524–532

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Student Team II, Grade 2009, Department of Oral Medicine, Fourth Military Medical University, No. 17 Changlexi Street, Xi’an, 710032, China

    Xinyu Qiu

  2. Department of Digestive Surgery, State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Jianyong Zheng

  3. Pathological Diagnosis and Research Center, The 302nd Hospital of PLA, Beijing, 100039, China

    Xiaodong Guo

  4. Department of Experimental Surgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China

    Xingchun Gao, Hui Liu & Yanyang Tu

  5. Department of Administrative, Tangdu Hospital, Fourth Military Medical University, Xi’an, 710038, China

    Yongsheng Zhang

Authors
  1. Xinyu Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianyong Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaodong Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xingchun Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanyang Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yongsheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yanyang Tu or Yongsheng Zhang.

Additional information

Xinyu Qiu and Jianyong Zheng offer the equal contribution to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qiu, X., Zheng, J., Guo, X. et al. Reduced expression of SOCS2 and SOCS6 in hepatocellular carcinoma correlates with aggressive tumor progression and poor prognosis. Mol Cell Biochem 378, 99–106 (2013). https://doi.org/10.1007/s11010-013-1599-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-013-1599-5

Keywords

Search

Navigation