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 (GC). SCNN1B mRNA expression was silenced commonly by promoter hypermethylation in GC cell lines and primary tumor tissues. Tissue microarray analysis revealed that high expression of SCNN1B was an independent prognostic factor for longer survival in GC 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 unfold protein response (UPR) via activation of PERK, ATF4, XBP1s and CHOP and leading in turn to caspase-dependent apoptosis. Accordingly, SCNN1B sensitized GC cells to the UPR-inducing drug tunicamycin. GRP78 overexpression abolished the inhibitory effect of SCNN1B on cell growth and migration, while GRP78 silencing aggravated growth inhibition by SCNN1B. In summary, our results identify SCNN1B as a tumor suppressor function that triggers UPR in GC cells, with implications for its potential clinical applications as a survival biomarker in GC patients.
- Received June 14, 2016.
- Revision received November 14, 2016.
- Accepted December 8, 2016.
- Copyright ©2017, American Association for Cancer Research.