title: HNF4α 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-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.
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Hae Ryung
authors.initials: HR
authors.lastname: Chang
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Seungyoon
authors.initials: S
authors.lastname: Nam
authors.affiliation: Department of Pathology, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Myeong-Cherl
authors.initials: MC
authors.lastname: Kook
authors.affiliation: Molecular Epidemiology Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Kim
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Hae Rim
authors.initials: HR
authors.lastname: Jung
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lemos
authors.affiliation: Animal Sciences Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Hye Hyun
authors.initials: HH
authors.lastname: Seo
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Hee Seo
authors.initials: HS
authors.lastname: Park
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Youme
authors.initials: Y
authors.lastname: Gim
authors.affiliation: Cancer Genomics Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Dongwan
authors.initials: D
authors.lastname: Hong
authors.affiliation: Department of Statistics, Seoul National University, Seoul, Republic of Korea.
authors.forename: Iksoo
authors.initials: I
authors.lastname: Huh
authors.affiliation: Gastric Cancer Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Young-Woo
authors.initials: YW
authors.lastname: Kim
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Tan
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA.
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.affiliation: Department of Statistics, Seoul National University, Seoul, Republic of Korea.
authors.forename: Taesung
authors.initials: T
authors.lastname: Park
authors.affiliation: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Liang
authors.affiliation: New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea.
authors.forename: Yon Hui
authors.initials: YH
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000230:Adenocarcinoma / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D044466:Asian People; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011897:Random Allocation; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D044465:White People; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein
chemical_list: D014408:Biomarkers, Tumor; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D055372:AMP-Activated Protein Kinases
keywords: DRUG DEVELOPMENT; GASTRIC CANCER; GENE EXPRESSION; MOLECULAR BIOLOGY; ONCOGENES