SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity

Nature Genetics
Hirohide YoshikawaJames G Herman

Abstract

Hepatocellular carcinoma (HCC) is a major cause of cancer death, but the molecular mechanism for its development beyond its initiation has not been well characterized. Suppressor of cytokine signaling (SOCS-1; also known as JAB and SSI-1) switches cytokine signaling 'off' by means of its direct interaction with Janus kinase (JAK). We identified aberrant methylation in the CpG island of SOCS-1 that correlated with its transcription silencing in HCC cell lines. The incidence of aberrant methylation was 65% in the 26 human primary HCC tumor samples analyzed. Moreover, the restoration of SOCS-1 suppressed both growth rate and anchorage-independent growth of cells in which SOCS-1 was methylation-silenced and JAK2 was constitutively activated. This growth suppression was caused by apoptosis and was reproduced by AG490, a specific, chemical JAK2 inhibitor that reversed constitutive phosphorylation of STAT3 in SOCS-1 inactivated cells. The high prevalence of the aberrant SOCS-1 methylation and its growth suppression activity demonstrated the importance of the constitutive activation of the JAK/STAT pathway in the development of HCC. Our results also indicate therapeutic strategies for the treatment of HCC including use of SOCS-1 in gen...Continue Reading

References

Nov 1, 1977·Cell·J R Paulson, U K Laemmli
Jun 19, 1992·International Journal of Cancer. Journal International Du Cancer·G RamponiG Camici
Nov 1, 1980·Cell·B VogelsteinD S Coffey
Oct 19, 1995·Nature·J N Ihle
Sep 29, 1995·Science·N N DanialP B Rothman
Oct 11, 1994·Proceedings of the National Academy of Sciences of the United States of America·J G HermanW M Linehan
Jan 28, 1994·Cell·T KishimotoS Akira
Sep 3, 1996·Proceedings of the National Academy of Sciences of the United States of America·J G HermanS B Baylin
May 1, 1997·BioTechniques·J A Kramer, S A Krawetz
Jun 26, 1997·Nature·R StarrD J Hilton
Nov 5, 1997·Biochemical and Biophysical Research Communications·M MasuharaA Yoshimura
Nov 14, 1997·Proceedings of the National Academy of Sciences of the United States of America·F B FurnariW K Cavenee
Feb 21, 1998·Proceedings of the National Academy of Sciences of the United States of America·D J HiltonN A Nicola
Jun 17, 1998·Proceedings of the National Academy of Sciences of the United States of America·J G HermanS B Baylin
Nov 25, 1998·Proceedings of the National Academy of Sciences of the United States of America·R StarrW S Alexander
Dec 23, 1998·Proceedings of the National Academy of Sciences of the United States of America·T NakaT Kishimoto
Aug 24, 1999·Cell·J F BrombergJ E Darnell

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Citations

Jun 27, 2006·Journal of Gastroenterology·Toshikazu UshijimaTakao Maekita
Sep 1, 2007·Hepatology International·Motohisa TadaOsamu Yokosuka
Jan 30, 2008·Cell Research·Khandaker Al Zaid Siddiquee, James Turkson
Oct 2, 2002·Nature Genetics·Giuseppe ZardoJoseph F Costello
Feb 18, 2004·Nature Reviews. Cancer·Hua Yu, Richard Jove
Feb 19, 2005·Nature Reviews. Cancer·Toshikazu Ushijima
Oct 3, 2002·Nature Reviews. Cancer·James E Darnell
May 26, 2007·Nature Reviews. Immunology·Akihiko YoshimuraMasato Kubo
May 23, 2003·Oncogene·Mohinder K SarnaPeta A Tilbrook
Feb 15, 2002·The Journal of Biological Chemistry·Sarmila MajumderSamson T Jacob
Sep 5, 2002·The Journal of Experimental Medicine·Takafumi YoshidaAkihiko Yoshimura
Jun 16, 2004·The Journal of Experimental Medicine·Takafumi YoshidaAkihiko Yoshimura
May 24, 2006·The Journal of Experimental Medicine·Toshikatsu HanadaAkihiko Yoshimura
Apr 1, 2009·The Journal of Experimental Medicine·Atsushi HosuiLothar Hennighausen
Aug 26, 2009·Diagnostic Molecular Pathology : the American Journal of Surgical Pathology, Part B·David WuJeffery L Kutok
May 23, 2012·Genome Research·Suhaida A SelamatIte A Laird-Offringa
Sep 5, 2008·Journal of Virology·Tatsuo KandaRatna B Ray
Jan 14, 2009·Molecular and Cellular Biology·Yuko ShikauchiHirohide Yoshikawa
Sep 29, 2005·Journal of Clinical Pathology·F FarabegoliM Taffurelli
Mar 23, 2004·Annual Review of Immunology·Warren S Alexander, Douglas J Hilton
Apr 12, 2005·Annual Review of Pharmacology and Toxicology·Manel Esteller
May 8, 2002·The Journal of Clinical Investigation·Jacqueline Bromberg
May 19, 2005·Arthritis Research & Therapy·Akihiko YoshimuraToshikatsu Hanada
Feb 23, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Pasquale Sansone, Jacqueline Bromberg
Sep 4, 2012·International Journal of Molecular Sciences·Sumiyo MoritaIzuho Hatada
Jan 8, 2008·World Journal of Gastroenterology : WJG·Michael HöpfnerHans Scherübl
Mar 20, 2008·World Journal of Gastroenterology : WJG·Juliette Martin, Jean-Francois Dufour
Feb 6, 2009·World Journal of Gastroenterology : WJG·Isabel Fabregat

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