CADM1 inhibits squamous cell carcinoma progression by reducing STAT3 activity

Sci Rep. 2016 Apr 1:6:24006. doi: 10.1038/srep24006.

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 α6β4 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Disease Progression
  • Female
  • Gene Expression Profiling
  • Humans
  • Immunoglobulins / genetics
  • Immunoglobulins / metabolism*
  • Integrin alpha6beta4 / metabolism
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Membrane Proteins / metabolism
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Nitriles
  • Pyrazoles / chemistry
  • Pyrimidines
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / pathology

Substances

  • CADM1 protein, human
  • Cadm1 protein, mouse
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules
  • Immunoglobulins
  • Integrin alpha6beta4
  • Membrane Proteins
  • Nitriles
  • Pyrazoles
  • Pyrimidines
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • ruxolitinib
  • ERBB2 protein, human
  • Erbb2 protein, mouse
  • Receptor, ErbB-2