Abstract
Background and objectives
Inflammation plays an important role in gastric cancer (GC) development and progression. Suppressor of cytokine signaling (SOCS)-1 and SOCS-3 negatively regulate proinflammatory cytokine signaling; however, their prognostic significance in GC remains unknown. We evaluated the clinicopathological correlation and prognostic significance of SOCS-1 and SOCS-3 in GC.
Methods
SOCS-1 and SOCS-3 mRNA levels were analyzed in 80 paired gastric tumor and adjacent normal mucosal tissues using a microarray dataset from the Gene Expression Omnibus. Univariate and multivariate analyses were performed to investigate the prognostic impact of SOCS-1 and SOCS-3 immunohistochemical expression on overall survival (OS) and relapse-free survival (RFS) in 186 consecutive GC patients who underwent curative surgery.
Results
SOCS-1 and SOCS-3 mRNA expression levels were lower in gastric tumor tissues than in matched normal mucosa. OS and RFS were significantly longer in the high SOCS-1 and SOCS-3 expression groups than in their corresponding low expression groups (p < 0.05). High simultaneous SOCS-1 and SOCS-3 expression were associated with longer OS compared with low simultaneous SOCS-1 and SOCS-3 expression (68.8 vs. 22.2 months; p < 0.001). SOCS-1 [hazards ratio (HR) 0.54, 95 % confidence interval (CI) 0.33–0.87, p = 0.011] and SOCS-3 (HR 0.46, 95 % CI 0.26–0.80, p = 0.006) were independent prognostic factors for OS. Only SOCS-1 (HR 0.20, 95 % CI 0.11–0.38, p = 0.006) was an independent prognostic factor for RFS.
Conclusion
Low SOCS-1 and SOCS-3 expression are poor prognostic indicators in GC. GC patients with low SOCS-1 and SOCS-3 expression need close follow-up.
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References
Bertuccio P, Chatenoud L, Levi F, Praud D, Ferlay J, Negri E et al (2009) Recent patterns in gastric cancer: a global overview. Int J Cancer 125:666–673
Chu PY, Yeh CM, Hsu NC, Chang YS, Chang JG, Yeh KT (2010) Epigenetic alteration of the SOCS1 gene in hepatocellular carcinoma. Swiss Med Wkly 140:w13065
Cooper JC, Shi M, Chueh FY, Venkitachalam S, Yu CL (2010) Enforced SOCS1 and SOCS3 expression attenuates Lck-mediated cellular transformation. Int J Oncol 36:1201–1208
Deng J, Jiao X, Liu H, Wu L, Zhang R, Wang B et al (2013) Lymph node metastasis is mediated by suppressor of cytokine signaling-3 in gastric cancer. Tumour Biol 34:3627–3636
Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM (2005) Gastric adenocarcinoma: review and considerations for future directions. Ann Surg 241:27–39
Fojtova M, Boudny V, Kovarik A, Lauerova L, Adamkova L, Souckova K et al (2007) Development of IFN-gamma resistance is associated with attenuation of SOCS genes induction and constitutive expression of SOCS 3 in melanoma cells. Br J Cancer 97:231–237
Galm O, Yoshikawa H, Esteller M, Osieka R, Herman JG (2003) SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma. Blood 101:2784–2788
Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899
He B, You L, Uematsu K, Zang K, Xu Z, Lee AY et al (2003) SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA 100:14133–14138
Huang FJ, Steeg PS, Price JE, Chiu WT, Chou PC, Xie K et al (2008) Molecular basis for the critical role of suppressor of cytokine signaling-1 in melanoma brain metastasis. Cancer Res 68:9634–9642
Inagaki-Ohara K, Kondo T, Ito M, Yoshimura A (2013) SOCS, inflammation, and cancer. JAK-STAT 2:e24053
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90
Jian-bo X, Hui W, Yu-long H, Chang-hua Z, Long-juan Z, Shi-rong C et al (2011) Astrocyte-elevated gene-1 overexpression is associated with poor prognosis in gastric cancer. Med Oncol 28:455–462
Komazaki T, Nagai H, Emi M, Terada Y, Yabe A, Jin E et al (2004) Hypermethylation-associated inactivation of the SOCS-1 gene, a JAK/STAT inhibitor, in human pancreatic cancers. Jpn J Clin Oncol 34:191–194
Komyod W, Bohm M, Metze D, Heinrich PC, Behrmann I (2007) Constitutive suppressor of cytokine signaling 3 expression confers a growth advantage to a human melanoma cell line. Mol Cancer Res 5:271–281
Leong GM, Moverare S, Brce J, Doyle N, Sjogren K, Dahlman-Wright K et al (2004) Estrogen up-regulates hepatic expression of suppressors of cytokine signaling-2 and -3 in vivo and in vitro. Endocrinology 145:5525–5531
Li Z, Metze D, Nashan D, Muller-Tidow C, Serve HL, Poremba C et al (2004) Expression of SOCS-1, suppressor of cytokine signalling-1, in human melanoma. J Invest Dermatol 123:737–745
Li G, Wang Z, Wang Z, Xu J, Cui J, Cai S et al (2013) Gastric cancer patients with Helicobacter pylori infection have a poor prognosis. J Surg Oncol 108:421–426
Liu WB, Ao L, Zhou ZY, Cui ZH, Zhou YH, Yuan XY et al (2010) CpG island hypermethylation of multiple tumor suppressor genes associated with loss of their protein expression during rat lung carcinogenesis induced by 3-methylcholanthrene and diethylnitrosamine. Biochem Biophys Res Commun 402:507–514
Oshimo Y, Kuraoka K, Nakayama H, Kitadai Y, Yoshida K, Chayama K et al (2004) Epigenetic inactivation of SOCS-1 by CpG island hypermethylation in human gastric carcinoma. Int J Cancer 112:1003–1009
Peek RM Jr, Crabtree JE (2006) Helicobacter infection and gastric neoplasia. J Pathol 208:233–248
Pierconti F, Martini M, Pinto F, Cenci T, Capodimonti S, Calarco A et al (2011) Epigenetic silencing of SOCS3 identifies a subset of prostate cancer with an aggressive behavior. Prostate 71:318–325
Raccurt M, Tam SP, Lau P, Mertani HC, Lambert A, Garcia-Caballero T et al (2003) Suppressor of cytokine signalling gene expression is elevated in breast carcinoma. Br J Cancer 89:524–532
Sakai I, Takeuchi K, Yamauchi H, Narumi H, Fujita S (2002) Constitutive expression of SOCS3 confers resistance to IFN-alpha in chronic myelogenous leukemia cells. Blood 100:2926–2931
Tischoff I, Hengge UR, Vieth M, Ell C, Stolte M, Weber A et al (2007) Methylation of SOCS-3 and SOCS-1 in the carcinogenesis of Barrett’s adenocarcinoma. Gut 56:1047–1053
Tokita T, Maesawa C, Kimura T, Kotani K, Takahashi K, Akasaka T et al (2007) Methylation status of the SOCS3 gene in human malignant melanomas. Int J Oncol 30:689–694
Tomic S, Chughtai N, Ali S (1999) SOCS-1, -2, -3: selective targets and functions downstream of the prolactin receptor. Mol Cell Endocrinol 158:45–54
Venkitachalam S, Chueh FY, Leong KF, Pabich S, Yu CL (2011) Suppressor of cytokine signaling 1 interacts with oncogenic lymphocyte-specific protein tyrosine kinase. Oncol Rep 25:677–683
Wang Z, Cai SR, He YL, Zhan WH, Chen CQ, Cui J et al (2009) High expression of PRL-3 can promote growth of gastric cancer and exhibits a poor prognostic impact on patients. Ann Surg Oncol 16:208–219
Yasukawa H, Sasaki A, Yoshimura A (2000) Negative regulation of cytokine signaling pathways. Annu Rev Immunol 18:143–164
Zhang J, Li H, Yu JP, Wang SE, Ren XB (2012) Role of SOCS1 in tumor progression and therapeutic application. Int J Cancer 130:1971–1980
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Grant Nos. 81101865 and 81272637) and Doctoral Fund of Ministry of Education of China (Grant No. 20110171120064).
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Guanghua Li and Jianbo Xu have contributed equally to this work.
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Li, G., Xu, J., Wang, Z. et al. Low expression of SOCS-1 and SOCS-3 is a poor prognostic indicator for gastric cancer patients. J Cancer Res Clin Oncol 141, 443–452 (2015). https://doi.org/10.1007/s00432-014-1838-5
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DOI: https://doi.org/10.1007/s00432-014-1838-5