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Background: Worldwide, gastric cancer (GC) 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 GC by identifying commonly dysregulated genes from the tumours of both Asian-Pacific and Caucasian patients. Methods: We generated transcriptomic profiles of 22 Caucasian GC tumours and their matched non-cancerous samples and performed an integrative analysis across different GC gene expression datasets. We examined the inhibition of commonly overexpressed oncogenes and their constituent signalling pathways by RNAi and/or pharmacological inhibition. Results: Hepatocyte nuclear factor-4a (HNF4a) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4a antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4a is downregulated by AMPKa signalling and the AMPK agonist metformin; blockade of HNF4a activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4a also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours. Conclusions: Our results indicate that HNF4a is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKa and resides upstream of WNT signalling. HNF4a may regulate 'metabolic switch' characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKa-HNF4a-WNT5A signalling cascade represents a potentially targetable pathway for drug development. [ABSTRACT FROM AUTHOR]