RT Journal Article
SR Electronic
T1 HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 19
OP 32
DO 10.1136/gutjnl-2014-307918
VO 65
IS 1
A1 Hae Ryung Chang
A1 Seungyoon Nam
A1 Myeong-Cherl Kook
A1 Kyung-Tae Kim
A1 Xiuping Liu
A1 Hui Yao
A1 Hae Rim Jung
A1 Robert Lemos, Jr
A1 Hye Hyun Seo
A1 Hee Seo Park
A1 Youme Gim
A1 Dongwan Hong
A1 Iksoo Huh
A1 Young-Woo Kim
A1 Dongfeng Tan
A1 Chang-Gong Liu
A1 Garth Powis
A1 Taesung Park
A1 Han Liang
A1 Yon Hui Kim
YR 2016
UL http://gut.bmj.com/content/65/1/19.abstract
AB 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-4α (HNF4α) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signalling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4α also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours.Conclusions Our results indicate that HNF4α is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPKα and resides upstream of WNT signalling. HNF4α may regulate ‘metabolic switch’ characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signalling cascade represents a potentially targetable pathway for drug development.