title: SOCS-3 is frequently methylated in head and neck squamous cell carcinoma and its precursor lesions and causes growth inhibition.
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.
authors: Department of Otorhinolaryngology, Head and Neck Surgery, University of Leipzig, Germany.
authors: Anette
authors: A
authors: Weber
authors: Ulrich R
authors: UR
authors: Hengge
authors: Walter
authors: W
authors: Bardenheuer
authors: Iris
authors: I
authors: Tischoff
authors: Florian
authors: F
authors: Sommerer
authors: Annett
authors: A
authors: Markwarth
authors: Andreas
authors: A
authors: Dietz
authors: Christian
authors: C
authors: Wittekind
authors: Andrea
authors: A
authors: Tannapfel
mesh_terms: D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000502:physiology*; D019175:DNA Methylation; D017931:DNA Primers; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008745:Methylation; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors