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Original article
HNF4α is a therapeutic target that links AMPK to WNT signalling in early-stage gastric cancer
  1. Hae Ryung Chang1,
  2. Seungyoon Nam1,
  3. Myeong-Cherl Kook2,
  4. Kyung-Tae Kim3,
  5. Xiuping Liu4,
  6. Hui Yao5,
  7. Hae Rim Jung1,
  8. Robert Lemos Jr6,
  9. Hye Hyun Seo7,
  10. Hee Seo Park1,
  11. Youme Gim1,
  12. Dongwan Hong8,
  13. Iksoo Huh9,
  14. Young-Woo Kim10,
  15. Dongfeng Tan11,
  16. Chang-Gong Liu4,
  17. Garth Powis6,
  18. Taesung Park9,
  19. Han Liang5,
  20. Yon Hui Kim1
  1. 1New Experimental Therapeutics Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea
  2. 2Department of Pathology, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea
  3. 3Molecular Epidemiology Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea
  4. 4Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  5. 5Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  6. 6Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California, USA
  7. 7Animal Sciences Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea
  8. 8Cancer Genomics Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea
  9. 9Department of Statistics, Seoul National University, Seoul, Republic of Korea
  10. 10Gastric Cancer Branch, National Cancer Center of Korea, Goyang-si, Kyeonggi-do, Republic of Korea
  11. 11Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
  1. Correspondence to Professor Yon Hui Kim, New Experimental Therapeutics Branch, National Cancer Center of Korea, Ilsan, Goyang-si, Gyeonggi-do 410-769, Republic of Korea; yhkim{at}ncc.re.kr; Professor Han Liang, The University of Texas MD Anderson Cancer Center, Houston TX, 77030, USA; hliang1@mdanderson.org; and Professor Taesung Park, Seoul National University, Kwanak-ro, Kwanak-gu Seoul, 151-742, Republic of Korea; tspark@stats.snu.ac.kr

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.

  • GASTRIC CANCER
  • DRUG DEVELOPMENT
  • ONCOGENES
  • MOLECULAR BIOLOGY
  • GENE EXPRESSION

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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