Research Paper Volume 11, Issue 23 pp 10839—10860

HIF-2α upregulation mediated by hypoxia promotes NAFLD-HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway

Jianxu Chen 1, *, , Jiandi Chen 2, *, , Jiaxin Huang 3, *, , Zhanyu Li 4, , Yihang Gong 1, , Baojia Zou 1, , Xialei Liu 1, , Lei Ding 1, , Peiping Li 1, , Zhiquan Zhu 5, , Baimeng Zhang 1, , Hui Guo 6, , Chaonong Cai 1, , Jian Li 1, ,

  • 1 Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
  • 2 Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
  • 3 Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
  • 4 Department of Pathology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
  • 5 Department of Thoracic Oncology, The Cancer Center of The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
  • 6 Department of Interventional Radiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
* Equal contribution

received: February 10, 2019 ; accepted: November 17, 2019 ; published: December 4, 2019 ;

https://doi.org/10.18632/aging.102488
How to Cite

Copyright © 2019 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a relevant risk factor for developing hepatocellular carcinoma (HCC). Steatohepatitic HCC (SH-HCC), characterized by HCC with steatosis, is influenced by lipid metabolism disorders. A hypoxic microenvironment is common in HCC and affects lipid metabolism. However, whether hypoxia-induced HIF-2α upregulation exacerbates lipid accumulation to contribute to SH-HCC progression remains unclear. In this study, we demonstrated that HIF-2α was elevated in tissues from NAFLD-HCC patients and was associated with survival. Under hypoxic conditions, upregulated HIF-2α was accompanied by lipid accumulation and PI3K-AKT-mTOR pathway activation. HIF-2α knockdown (KD) in steatotic HCC ameliorated triglyceride accumulation and steatosis. HIF-2α-KD steatotic HCC showed minimal lipid synthesis in a hypoxic environment, which contributes to a reduction in malignant behaviours. However, treatment with MHY1485 restored these behaviours. STAM mice, a mouse model that develops NAFLD-HCC, exhibit more rapid tumour progression upon exposure to hypoxia. STAM mice treated with INK-128 presented abrogated mTOR expression and tumour progression under hypoxic conditions with lower triglycerides and steatosis. In conclusion, in a hypoxic microenvironment, HIF-2α upregulation promotes steatotic HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway. Therefore, HIF-2α can be a biomarker and target in developing specific therapeutic measures for NAFLD-HCC patients.

Abbreviations

HCC: Hepatocellular carcinoma; SH-HCC: steatohepatitic HCC; NAFLD: Nonalcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; FA: fatty acid; HIF: hypoxia-inducible transcription factors; PHD: oxygen-dependent prolyl hydroxylase domain; FBS: fetal bovine serum; qPCR: quantitative PCR.