Sodium channel subunit SCNN1B suppresses gastric cancer growth and metastasis via GRP78 degradation

Yun Qian, Chi Chun Wong, Jiaying Xu, Huarong Chen, Yanquan Zhang, Wei Kang, Hua Wang, Li Zhang, Weilin Li, Eagle S.H. Chu, Minnie Y.Y. Go, Philip W.Y. Chiu, Enders K.W. Ng, Francis K.L. Chan, Joseph J.Y. Sung, Jianmin Si, Jun Yu

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish
Pages (from-to)1968-1982
Number of pages15
JournalCancer Research
Volume77
Issue number8
DOIs
StatePublished - Apr 15 2017

Bibliographical note

Funding Information:
This project was supported by research funds from RGC-GRF (14114615 and 766613) from Hong Kong; ShenzhenMunicipal Science and Technology R & D Fund (JCYJ20130401151108652), and Shenzhen Virtual University Park Support Scheme to CUHK Shenzhen Research Institute; National Natural Science Foundation of China (NSFC; 81502064); and Direct grant for Research 2013/2014, CUHK (4054100).

Publisher Copyright:
© 2017 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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