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Hnf4α Is Possibly the Missing Link Between Epithelial–Mesenchymal Transition and Warburg Effect During Hepatocarcinogenesis Publisher Pubmed



Shokouhian B1, 2 ; Negahdari B1 ; Heydari Z2 ; Totonchi M3 ; Aboulkheyr Es H4 ; Piryaei A5, 6 ; Mostafavi E7, 8 ; Vosough M2, 9
Authors
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Authors Affiliations
  1. 1. Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
  3. 3. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
  4. 4. School of Biomedical Engineering, University of Technology Sydney, Sydney, Australia
  5. 5. Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  6. 6. Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  7. 7. Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
  8. 8. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
  9. 9. Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden

Source: Cancer Science Published:2023


Abstract

Hepatocellular carcinoma (HCC) is a heterogeneous, late-diagnosed, and highly recurrent malignancy that often affects the whole body's metabolism. Finding certain theranostic molecules that can address current concerns simultaneously is one of the priorities in HCC management. In this study, performing protein–protein interaction network analysis proposed hepatocyte nuclear factor 4 alpha (HNF4α) as a hub protein, associating epithelial–mesenchymal transition (EMT) to reprogrammed cancer metabolism, formerly known as the Warburg effect. Both phenomena improved the compensation of cancerous cells in competitive conditions. Mounting evidence has demonstrated that HNF4α is commonly downregulated and serves as a tumor suppressor in the HCC. Enhancing the HNF4α mRNA translation through a specific synthetic antisense long non-coding RNA, profoundly affects both EMT and onco-metabolic modules in HCC cells. HNF4α overexpression decreased featured mesenchymal transcription factors and improved hepatocytic function, decelerated glycolysis, accelerated gluconeogenesis, and improved dysregulated cholesterol metabolism. Moreover, HNF4α overexpression inhibited the migration, invasion, and proliferation of HCC cells and decreased metastasis rate and tumor growth in xenografted nude mice. Our findings suggest a central regulatory role for HNF4α through its broad access to a wide variety of gene promoters involved in EMT and the Warburg effect in human hepatocytes. This essential impact indicates that HNF4α may be a potential target for HCC treatment. © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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