SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition

Oncogene. 2005 Oct 6;24(44):6699-708. doi: 10.1038/sj.onc.1208818.


The suppressors of cytokine signaling (SOCS) are inhibitors of cytokine signaling that function via the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. Recently, methylation of SOCS-1 and SOCS-3 has been implicated in the tumorigenesis of liver and lung cancer. This study was performed to elucidate the role of SOCS-1 and SOCS-3 in squamous cell carcinoma of the head and neck (HNSCC) and its precursor lesions. HNSCC of 94 patients and corresponding normal mucosa, lymph node metastases as well as 16 high- and 21 low-grade squamous cell dysplasias were studied by using methylation-specific PCR (MSP) for the SOCS-1 and SOCS-3 promoter after microdissection. The presence of SOCS-3 mRNA transcripts was confirmed by semiquantitative real-time PCR, and the SOCS-3 protein was analysed immunohistochemically. SOCS-3 hypermethylation was found in 85/94 HNSCC (90%) and in 10/16 high-grade and 9/21 low-grade dysplasias (63 and 43%, respectively). SOCS-1 promoter hypermethylation was detected in 10/94 HNSCC samples (11%) and in 2/16 high-grade and 1/21 low-grade dysplasias (13 and 5%, respectively). Lymph node metastases exhibited an identical methylation status as the primary tumors. Methylation of the SOCS-3 promoter correlated with downregulation of SOCS-3 transcripts and protein expression in these tumors and various cell lines. In the cell lines tested, SOCS-3 and SOCS-1 transcripts increased upon treatment with the demethylation compound 5-aza-2-deoxycytidine (5-AZA-DC). Overexpression of wild-type SOCS-3 in carcinoma cells with methylated SOCS-3 resulted in the induction of apoptosis and growth suppression as well as downregulation of STAT3, bcl-2 as well as bcl-xL. Our data suggest that promoter methylation and subsequent transcript downregulation of SOCS-3 transcripts and, to a much lesser extent, SOCS-1 are involved in the multistep carcinogenesis of HNSCC. During its involvement in tumor growth, restoration of SOCS-3 may hold treatment potential for HNSCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Division / physiology*
  • DNA Methylation
  • DNA Primers
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Methylation
  • RNA, Messenger / genetics
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Repressor Proteins / physiology
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology
  • Tumor Cells, Cultured


  • DNA Primers
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Repressor Proteins
  • SOCS1 protein, human
  • SOCS3 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Transcription Factors