Decreased Expression of the Suppressor of Cytokine Signaling 6 in Human Hepatocellular Carcinoma

  • Bae, Hyun-Jin (Department of Pathology, Microdissection Genomics Research Center, College of Medicine, The Catholic University of Korea) ;
  • Noh, Ji-Heon (Department of Pathology, Microdissection Genomics Research Center, College of Medicine, The Catholic University of Korea) ;
  • Eun, Jung-Woo (Department of Pathology, Microdissection Genomics Research Center, College of Medicine, The Catholic University of Korea) ;
  • Kim, Jeong-Kyu (Department of Pathology, Microdissection Genomics Research Center, College of Medicine, The Catholic University of Korea) ;
  • Jung, Kwang-Hwa (Department of Pathology, Microdissection Genomics Research Center, College of Medicine, The Catholic University of Korea) ;
  • Xie, Hong Jian (Department of Pathology, Microdissection Genomics Research Center, College of Medicine, The Catholic University of Korea) ;
  • Ahn, Young-Min (Department of the Kidney System, College of Oriental Medicine, Kyung Hee University) ;
  • Ryu, Jae-Chun (Department of the Kidney System, College of Oriental Medicine, Kyung Hee University) ;
  • Park, Won-Sang (Department of Pathology, Microdissection Genomics Research Center, College of Medicine, The Catholic University of Korea) ;
  • Lee, Jung-Young (Department of Pathology, Microdissection Genomics Research Center, College of Medicine, The Catholic University of Korea) ;
  • Nam, Suk-Woo (Department of Pathology, Microdissection Genomics Research Center, College of Medicine, The Catholic University of Korea)
  • Published : 2009.09.30

Abstract

Suppressors of cytokine signaling (SOCS) proteins were originally identified as negative feedback regulators of cytokine signaling and include the Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathways. Recent studies have shown that SOCS proteins negatively regulate the receptor tyrosine kinase (RTK) pathway including the insulin receptor (IR), EGFR, and KIT signaling pathways. In addition, SOCS1 and SOCS3 have been reported to have anti-tumor effects in human hepatocellular carcinoma (HCC). However, it is uncertain whether other members of the SOCS family are associated with tumor development and progression. In this study, to investigate whether SOCS6 is aberrantly regulated in HCC, we examined the expression level of SOCS6 in HCC by Western blot analysis and immunohistochemical staining. The results showed that SOCS6 was down-regulated in all examined HCCs compared to the corresponding normal tissues. In addition, expression of SOCS6 was observed in the cytoplasm of most normal and precancerous tissue, but not in the HCCs by immunohistochemical staining. This is first report to demonstrate that SOCS6 is aberrantly regulated in HCC. These findings suggest that underexpression of SOCS6 is involved in hepatocarcinogenesis, and SOCS6 may play a role, as a tumor suppressor, in HCC development and progression.

Keywords

References

  1. Bruix, J., Boix, L., Sala, M. & Llovet, J. M. Focus on hepatocellular carcinoma. Cancer Cell 5:215-219 (2004) https://doi.org/10.1016/S1535-6108(04)00058-3
  2. Farazi, P. A. & DePinho, R. A. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674-687 (2006) https://doi.org/10.1038/nrc1934
  3. de La Coste, A. et al. Somatic mutations of the betacatenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 95: 8847-8851 (1998) https://doi.org/10.1073/pnas.95.15.8847
  4. Pang, A., Ng, I. O., Fan, S. T. & Kwong, Y. L. Clinicopathologic significance of genetic alterations in hepatocellular carcinoma. Cancer Genet Cytogenet 146:8-15 (2003) https://doi.org/10.1016/S0165-4608(03)00103-1
  5. Satoh, S. et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 24:245-250 (2000) https://doi.org/10.1038/73448
  6. Thorgeirsson, S. S. & Grisham, J. W. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31:339-346 (2002) https://doi.org/10.1038/ng0802-339
  7. Krebs, D. L. & Hilton, D. J. SOCS: physiological suppressors of cytokine signaling. J Cell Sci 113 (Pt 16):2813-2819 (2000)
  8. Endo, T. A. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387:921-924 (1997) https://doi.org/10.1038/43213
  9. Naka, T. et al. Structure and function of a new STATinduced STAT inhibitor. Nature 387:924-929 (1997) https://doi.org/10.1038/43219
  10. Zhang, J. G. et al. The conserved SOCS box motif in suppressors of cytokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. Proc Natl Acad Sci USA 96:2071-2076 (1999) https://doi.org/10.1073/pnas.96.5.2071
  11. Emanuelli, B. et al. SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 275:15985-15991 (2000) https://doi.org/10.1074/jbc.275.21.15985
  12. Kario, E. et al. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J Biol Chem 280:7038-7048 (2005) https://doi.org/10.1074/jbc.M408575200
  13. Bayle, J. et al. Suppressor of cytokine signaling 6 associates with KIT and regulates KIT receptor signaling. J Biol Chem 279:12249-12259 (2004) https://doi.org/10.1074/jbc.M313381200
  14. Masuhara, M. et al. Cloning and characterization of novel CIS family genes. Biochem Biophys Res Commun 239:439-446 (1997) https://doi.org/10.1006/bbrc.1997.7484
  15. Bayle, J. et al. The E3 ubiquitin ligase HOIL-1 induces the polyubiquitination and degradation of SOCS6 associated proteins. FEBS Lett 580:2609-2614 (2006) https://doi.org/10.1016/j.febslet.2006.03.093
  16. Mooney, R. A. et al. Suppressors of cytokine signaling-1 and -6 associate with and inhibit the insulin receptor. A potential mechanism for cytokine-mediated insulin resistance. J Biol Chem 276:25889-25893 (2001) https://doi.org/10.1074/jbc.M010579200
  17. Yoshikawa, H. 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 28:29-35 (2001) https://doi.org/10.1038/ng0501-29
  18. Niwa, Y. et al. 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 (2005) https://doi.org/10.1038/sj.onc.1208788
  19. Calvisi, D. F. et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130:1117-1128 (2006) https://doi.org/10.1053/j.gastro.2006.01.006
  20. Ogata, H. et al. Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Gastroenterology 131:179-193 (2006) https://doi.org/10.1053/j.gastro.2006.04.025
  21. Liu, L. et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 66:11851-11858 (2006) https://doi.org/10.1158/0008-5472.CAN-06-1377
  22. Toniato, E. et al. TRIM8/GERP RING finger protein interacts with SOCS-1. J Biol Chem 277:37315-37322 (2002) https://doi.org/10.1074/jbc.M205900200
  23. Haan, S. et al. Tyrosine phosphorylation disrupts elongin interaction and accelerates SOCS3 degradation. J Biol Chem 278:31972-31979 (2003) https://doi.org/10.1074/jbc.M303170200
  24. Li, L. et al. Insulin induces SOCS-6 expression and its binding to the p85 monomer of phosphoinositide 3-kinase, resulting in improvement in glucose metabolism. J Biol Chem 279:34107-34114 (2004) https://doi.org/10.1074/jbc.M312672200
  25. Kamizono, S. et al. The SOCS box of SOCS-1 accelerates ubiquitin-dependent proteolysis of TEL-JAK2. J Biol Chem 276:12530-12538 (2001) https://doi.org/10.1074/jbc.M010074200
  26. Orr, S. J. et al. CD33 responses are blocked by SOCS3 through accelerated proteasomal-mediated turnover. Blood 109:1061-1068 (2007) https://doi.org/10.1182/blood-2006-05-023556
  27. Orr, S. J. et al. SOCS3 targets Siglec 7 for proteasomal degradation and blocks Siglec 7-mediated responses. J Biol Chem 282:3418-3422 (2007) https://doi.org/10.1074/jbc.C600216200