PubAg

Main content area

MUC16 mutation predicts a favorable clinical outcome and correlates decreased Warburg effect in gastric cancer

Author:
Zhao, Huijin, Zhang, Lan
Source:
Biochemical and biophysical research communications 2018 v.506 no.4 pp. 780-786
ISSN:
0006-291X
Subject:
Western blotting, acidification, autophagy, carcinogenesis, gene expression regulation, genomics, glucose, glycolysis, lactic acid, loss-of-function mutation, nutrient transport, oncogenes, patients, prognosis, protein content, somatic mutation, stomach neoplasms, transcription factors
Abstract:
Mutations in oncogenes or tumor suppressors can reprogram tumor metabolism by controlling multiple metabolic changes including glycolysis, glutaminolysis, increased autophagy, and macropinocytosis. Somatic mutations are essential for the development and growth of gastric cancer (GC), but the precise roles of these mutations in GC glucose metabolism remain largely unknown. In this study, we examined cancer genomes in 375 GC samples and demonstrated several glycolysis-related mutations in GC. Of note, loss-of-function mutation in MUC16 gene was identified. Mutated MUC16 predicted a better prognosis in GC patients. Gene set enrichment analysis suggested that mutated MUC16 status was associated with down-regulation of PI3K/Akt/mTOR signaling and Myc expression. GC cells with MUC16 mutations had reduced glycolytic capacity. Subsequently, genetic silencing of MUC16 in SNU16 and SNU5 cells led to significant reduction in glucose uptake, lactate production, extracellular acidification rate, and colony formation ability, indicating the critical regulatory roles of MUC16 in GC glycolysis and tumorigenesis. Specifically, western blotting showed that MUC16 knockdown inhibited PI3K/Akt/mTOR signaling, and reduced the protein level of Myc, which acts as a key transcription factor in regulating glycolysis. Taken together, our findings identify the MUC16-PI3K/Akt/mTOR-Myc axis as a critical signaling cascade that couples genomic mutations to metabolic reprogramming in GC.
Agid:
6225409