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.
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Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics. CA Cancer J Clin 55:74–108
Bruix J, Sherman M (2005) Management of hepatocellular carcinoma. Hepatology 42:1208–1236
El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132:2557–2576
Fujimoto M, Naka T (2003) Regulation of cytokine signaling by SOCS family molecules. Trends Immunol 24:659–666
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
Elliott J, Johnston JA (2004) SOCS: role in inflammation, allergy and homeostasis. Trends Immunol 25:434–440
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
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
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
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
Jegalian AG, Wu H (2002) Differential roles of SOCS family members in EpoR signal transduction. J Interferon Cytokine Res 22:853–860
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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Xinyu Qiu and Jianyong Zheng offer the equal contribution to this study.
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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
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DOI: https://doi.org/10.1007/s11010-013-1599-5