Dataset Information

HNF4? is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer.

ABSTRACT:

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-4? (HNF4?) upregulation was a key signalling event in gastric tumours from both Caucasian and Asian patients, and HNF4? antagonism was antineoplastic. Perturbation experiments in GC tumour cell lines and xenograft models further demonstrated that HNF4? is downregulated by AMPK? signalling and the AMPK agonist metformin; blockade of HNF4? activity resulted in cyclin downregulation, cell cycle arrest and tumour growth inhibition. HNF4? also regulated WNT signalling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumours.

Conclusions

Our results indicate that HNF4? is a targetable oncoprotein in GC, is regulated by AMPK signalling through AMPK? and resides upstream of WNT signalling. HNF4? may regulate 'metabolic switch' characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPK?-HNF4?-WNT5A signalling cascade represents a potentially targetable pathway for drug development.

SUBMITTER: Chang HR

PROVIDER: S-EPMC4717359 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer.

Chang Hae Ryung HR Nam Seungyoon S Kook Myeong-Cherl MC Kim Kyung-Tae KT Liu Xiuping X Yao Hui H Jung Hae Rim HR Lemos Robert R Seo Hye Hyun HH Park Hee Seo HS Gim Youme Y Hong Dongwan D Huh Iksoo I Kim Young-Woo YW Tan Dongfeng D Liu Chang-Gong CG Powis Garth G Park Taesung T Liang Han H Kim Yon Hui YH

Gut 20141119 1

<h4>Background</h4>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.<h4>Objective</h4>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.<h4>Methods</h4>We generated transcriptomic profiles ...[more]

PMID: 25410163

Similar Datasets

Project description: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 HNF4α upregulation was a key signaling event in gastric tumors from both Caucasian and Asian patients, and HNF4α antagonism was antineoplastic. Perturbation experiments in GC tumor cell lines and xenograft models further demonstrated that HNF4α is downregulated by AMPKα signaling and the AMPK agonist metformin; blockade of HNF4α activity resulted in cyclin downregulation, cell cycle arrest, and tumor growth inhibition. HNF4α also regulated WNT signaling through its target gene WNT5A, a potential prognostic marker of diffuse type gastric tumors. Conclusions Our results indicate that HNF4α is a targetable oncoprotein in gastric cancer, is regulated by AMPK signaling through AMPKα, and resides upstream of WNT signaling. HNF4α may regulate “metabolic switch” characteristic of a general malignant phenotype and its target WNT5A has potential prognostic values. The AMPKα-HNF4α-WNT5A signaling cascade represents a potentially targetable pathway for drug development. 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.