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

Oncogene volume 24, pages 6699–6708 (2005)Cite this article

Abstract

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.

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Abbreviations

HNSCC:

head and neck squamous cell carcinoma

SOCS:

suppressor of cytokine signaling

STAT:

signal transducer and activator of transcription

JAK:

Janus kinase

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Acknowledgements

This paper was supported by the Bundesministerium für Bildung und Forschung (BMB+F), Interdisciplinary Centre for Clinical Research (IZKF) at the University of Leipzig (01KS9504/1, project D01).

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Author notes

  1. Anette Weber, Ulrich R Hengge and Walter Bardenheuer: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Otorhinolaryngology, Head and Neck Surgery, University of Leipzig, Leipzig, D-04103, Germany

    Anette Weber & Andreas Dietz

  2. Department of Dermatology, Heinrich-Heine-University, Düsseldorf, D-40225, Germany

    Ulrich R Hengge & Walter Bardenheuer

  3. Institute of Pathology, University of Leipzig, Leipzig, D-04103, Germany

    Iris Tischoff, Florian Sommerer, Annett Markwarth, Christian Wittekind & Andrea Tannapfel

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  1. Anette Weber
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Correspondence to Andrea Tannapfel.

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Weber, A., Hengge, U., Bardenheuer, W. et al. SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition. Oncogene 24, 6699–6708 (2005). https://doi.org/10.1038/sj.onc.1208818

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