Sodium Channel Subunit SCNN1B Suppresses Gastric Cancer Growth and Metastasis via GRP78 Degradation

Cancer Res. 2017 Apr 15;77(8):1968-1982. doi: 10.1158/0008-5472.CAN-16-1595. Epub 2017 Feb 15.

Abstract

There remains a paucity of functional biomarkers in gastric cancer. Here, we report the identification of the sodium channel subunit SCNN1B as a candidate biomarker in gastric cancer. SCNN1B mRNA expression was silenced commonly by promoter hypermethylation in gastric cancer cell lines and primary tumor tissues. Tissue microarray analysis revealed that high expression of SCNN1B was an independent prognostic factor for longer survival in gastric cancer patients, especially those with late-stage disease. Functional studies demonstrated that SCNN1B overexpression was sufficient to suppress multiple features of cancer cell pathophysiology in vitro and in vivo Mechanistic investigations revealed that SCNN1B interacted with the endoplasmic reticulum chaperone, GRP78, and induced its degradation via polyubiquitination, triggering the unfolded protein response (UPR) via activation of PERK, ATF4, XBP1s, and C/EBP homologous protein and leading in turn to caspase-dependent apoptosis. Accordingly, SCNN1B sensitized gastric cancer cells to the UPR-inducing drug tunicamycin. GRP78 overexpression abolished the inhibitory effect of SCNN1B on cell growth and migration, whereas GRP78 silencing aggravated growth inhibition by SCNN1B. In summary, our results identify SCNN1B as a tumor-suppressive function that triggers UPR in gastric cancer cells, with implications for its potential clinical applications as a survival biomarker in gastric cancer patients. Cancer Res; 77(8); 1968-82. ©2017 AACR.

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Biomarkers, Tumor / biosynthesis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Cycle Checkpoints / physiology
  • Cell Growth Processes / physiology
  • Cell Movement / physiology
  • DNA Methylation
  • Down-Regulation
  • Epithelial Sodium Channels / biosynthesis
  • Epithelial Sodium Channels / genetics
  • Epithelial Sodium Channels / metabolism*
  • Female
  • Gene Knockdown Techniques
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Heterografts
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Metastasis
  • Promoter Regions, Genetic
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • Tissue Array Analysis
  • Ubiquitination

Substances

  • Biomarkers, Tumor
  • Epithelial Sodium Channels
  • Heat-Shock Proteins
  • SCNN1B protein, human
  • molecular chaperone GRP78