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

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.

• Authors: Huijin Zhao, Lan Zhang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 506 Issue 4 Pg. 780-786 (12 02 2018) ISSN: 1090-2104 [Electronic] United States
• PMID: 30389134 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• CA-125 Antigen
• MUC16 protein, human
• Membrane Proteins

Topics

• Adenocarcinoma (genetics, metabolism, pathology)
• CA-125 Antigen (genetics)
• Cell Line, Tumor
• Gene Silencing
• Glycolysis
• Humans
• Membrane Proteins (genetics)
• Mutation (genetics)
• Phenotype
• Prognosis
• Stomach Neoplasms (genetics, metabolism, pathology)
• Treatment Outcome