TY - JOUR
T1 - Sodium channel subunit SCNN1B suppresses gastric cancer growth and metastasis via GRP78 degradation
AU - Qian, Yun
AU - Wong, Chi Chun
AU - Xu, Jiaying
AU - Chen, Huarong
AU - Zhang, Yanquan
AU - Kang, Wei
AU - Wang, Hua
AU - Zhang, Li
AU - Li, Weilin
AU - Chu, Eagle S.H.
AU - Go, Minnie Y.Y.
AU - Chiu, Philip W.Y.
AU - Ng, Enders K.W.
AU - Chan, Francis K.L.
AU - Sung, Joseph J.Y.
AU - Si, Jianmin
AU - Yu, Jun
N1 - Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/4/15
Y1 - 2017/4/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-16-1595
DO - 10.1158/0008-5472.CAN-16-1595
M3 - Article
C2 - 28202509
AN - SCOPUS:85018816340
SN - 0008-5472
VL - 77
SP - 1968
EP - 1982
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -
