GSE63288
HNF4a is a therapeutic target that links AMPK to WNT signaling in early-stage gastric cancer
Background Worldwide, gastric cancer is the fourth most common malignancy and the most common cancer in East Asia. Development of targeted therapies for this disease has focused on a few known oncogenes but has had limited effects. Objective To determine oncogenic mechanisms and novel therapeutic targets specific for gastric cancer by identifying commonly dys-regulated genes from the tumors of both Asian-Pacific and Caucasian patients. Design We generated transcriptomic profiles of 22 Caucasian gastric cancer tumors and their matched non-cancerous samples, and performed an integrative analysis across different gastric cancer gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signaling pathways by RNAi and/or pharmacologic inhibition. Results We found that HNF4a upregulation was a key signaling event in gastric tumors from both Caucasian and Asian patients, and HNF4a antagonism was antineoplastic. Perturbation experiments in GC tumor cell lines and xenograft models further demonstrated that HNF4a is downregulated by AMPKa signaling and the AMPK agonist metformin; blockade of HNF4a activity resulted in cyclin downregulation, cell cycle arrest, and tumor growth inhibition. HNF4a also regulated WNT signaling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumors. Conclusions Our results indicate that HNF4a is a targetable oncoprotein in gastric cancer, is regulated by AMPK signaling through AMPKa, and resides upstream of WNT signaling. HNF4a may regulate “metabolic switch” characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKa-HNF4a-WNT5A signaling cascade represents a potentially targetable pathway for drug development. Overall design: Integrative analysis of Caucasian and Asian-Pacific gastric tumor expression datasets (including newly generated transcriptomic profiling of 22 tumors in this study) revealed a relatively small common sets of highly overexpressed genes.