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CADM1 inhibits squamous cell carcinoma progression by reducing STAT3 activity.

ABSTRACT: Although squamous cell carcinomas (SqCCs) of the lungs, head and neck, oesophagus, and cervix account for up to 30% of cancer deaths, the mechanisms that regulate disease progression remain incompletely understood. Here, we use gene transduction and human tumor xenograft assays to establish that the tumour suppressor Cell adhesion molecule 1 (CADM1) inhibits SqCC proliferation and invasion, processes fundamental to disease progression. We determine that the extracellular domain of CADM1 mediates these effects by forming a complex with HER2 and integrin ?6?4 at the cell surface that disrupts downstream STAT3 activity. We subsequently show that treating CADM1 null tumours with the JAK/STAT inhibitor ruxolitinib mimics CADM1 gene restoration in preventing SqCC growth and metastases. Overall, this study identifies a novel mechanism by which CADM1 prevents SqCC progression and suggests that screening tumours for loss of CADM1 expression will help identify those patients most likely to benefit from JAK/STAT targeted chemotherapies.

SUBMITTER: Vallath S

PROVIDER: S-EPMC4817512 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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CADM1 inhibits squamous cell carcinoma progression by reducing STAT3 activity.

Vallath Sabari S Sage Elizabeth K EK Kolluri Krishna K KK Lourenco Sofia N SN Teixeira Vitor S VS Chimalapati Suneeta S George P Jeremy PJ Janes Sam M SM Giangreco Adam A

Scientific reports 20160401

Although squamous cell carcinomas (SqCCs) of the lungs, head and neck, oesophagus, and cervix account for up to 30% of cancer deaths, the mechanisms that regulate disease progression remain incompletely understood. Here, we use gene transduction and human tumor xenograft assays to establish that the tumour suppressor Cell adhesion molecule 1 (CADM1) inhibits SqCC proliferation and invasion, processes fundamental to disease progression. We determine that the extracellular domain of CADM1 mediates ...[more]

PMID: 27035095

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Project description:BackgroundSerine hydroxymethyltransferase 2 (SHMT2) is a vital metabolic enzyme in one carbon metabolism catalyzing the conversion of serine to glycine, which has been reported to play a crucial role in the progression of tumors. However, its function in tongue squamous cell carcinoma (TSCC) remains unclear.MethodsSHMT2 expression was analyzed using samples in online databases, and was assessed through immunohistochemistry staining of collected clinical specimens. The correlation between SHMT2 expression and the cell cycle was predicted through bioinformatic analysis, including weighted gene co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA). After transfection with siRNA, CCK8 assay, Edu staining, flow cytometry, trans-well assay, and wound healing experiments were performed to verify the functional role of SHMT2 in vitro. A stable cell line with SHMT2 silencing was established to detect the oncogenic function of SHMT2 in vivo.ResultsThe expression of SHMT2 was up-regulated in TSCC tissues and cell lines compared with normal groups, and highly expressed SHMT2 significantly indicated a poorer clinical outcome for TSCC patients. Bioinformatic analysis found that high expression of SHMT2 was closely related with biologic process including cell cycle and cell cycle G1/S transition. Down regulating of SHMT2 significantly suppressed the proliferation, invasive and migrative ability of TSCC cells, and induced the prolongation of the G1 phase of the cell cycle in vitro. Furthermore, western blot showed that cell cycle-related regulators such as cyclin-dependent kinase 4 (CDK4) and cyclinD1 expression levels were decreased, while the expression levels of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 were increased after SHMT2 knockdown. Silencing SHMT2 in the HN6 cell line using short hairpin RNA also impeded tumor growth in vivo.ConclusionsOverexpression of SHMT2 in TSCC indicated low survival rates, and was associated with aggressive behaviors of TSCC. It was also found to be involved in cell cycle regulation of TSCC cells. SHMT2 may serve as a novel prognostic indicator of TSCC.

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CADM1 inhibits squamous cell carcinoma progression by reducing STAT3 activity.

Publications

CADM1 inhibits squamous cell carcinoma progression by reducing STAT3 activity.

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