PMID- 31796646
OWN - NLM
STAT- MEDLINE
DCOM- 20201009
LR  - 20211204
IS  - 1945-4589 (Electronic)
IS  - 1945-4589 (Linking)
VI  - 11
IP  - 23
DP  - 2019 Dec 4
TI  - HIF-2alpha upregulation mediated by hypoxia promotes NAFLD-HCC progression by 
      activating lipid synthesis via the PI3K-AKT-mTOR pathway.
PG  - 10839-10860
LID - 10.18632/aging.102488 [doi]
AB  - 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-2alpha upregulation exacerbates lipid 
      accumulation to contribute to SH-HCC progression remains unclear. In this study, 
      we demonstrated that HIF-2alpha was elevated in tissues from NAFLD-HCC patients and 
      was associated with survival. Under hypoxic conditions, upregulated HIF-2alpha was 
      accompanied by lipid accumulation and PI3K-AKT-mTOR pathway activation. HIF-2alpha 
      knockdown (KD) in steatotic HCC ameliorated triglyceride accumulation and 
      steatosis. HIF-2alpha-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-2alpha upregulation 
      promotes steatotic HCC progression by activating lipid synthesis via the 
      PI3K-AKT-mTOR pathway. Therefore, HIF-2alpha can be a biomarker and target in 
      developing specific therapeutic measures for NAFLD-HCC patients.
FAU - Chen, Jianxu
AU  - Chen J
AD  - Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen 
      University, Zhuhai, China.
FAU - Chen, Jiandi
AU  - Chen J
AD  - Department of Endocrinology, The Fifth Affiliated Hospital of Sun Yat-sen 
      University, Zhuhai, China.
FAU - Huang, Jiaxin
AU  - Huang J
AD  - Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan 
      University, Chengdu, China.
FAU - Li, Zhanyu
AU  - Li Z
AD  - Department of Pathology, The Fifth Affiliated Hospital of Sun Yat-sen University, 
      Zhuhai, China.
FAU - Gong, Yihang
AU  - Gong Y
AD  - Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen 
      University, Zhuhai, China.
FAU - Zou, Baojia
AU  - Zou B
AD  - Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen 
      University, Zhuhai, China.
FAU - Liu, Xialei
AU  - Liu X
AD  - Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen 
      University, Zhuhai, China.
FAU - Ding, Lei
AU  - Ding L
AD  - Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen 
      University, Zhuhai, China.
FAU - Li, Peiping
AU  - Li P
AD  - Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen 
      University, Zhuhai, China.
FAU - Zhu, Zhiquan
AU  - Zhu Z
AD  - Department of Thoracic Oncology, The Cancer Center of The Fifth Affiliated 
      Hospital of Sun Yat-sen University, Zhuhai, China.
FAU - Zhang, Baimeng
AU  - Zhang B
AD  - Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen 
      University, Zhuhai, China.
FAU - Guo, Hui
AU  - Guo H
AD  - Department of Interventional Radiology, The Fifth Affiliated Hospital of Sun 
      Yat-sen University, Zhuhai, China.
FAU - Cai, Chaonong
AU  - Cai C
AD  - Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen 
      University, Zhuhai, China.
FAU - Li, Jian
AU  - Li J
AD  - Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-sen 
      University, Zhuhai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20191204
PL  - United States
TA  - Aging (Albany NY)
JT  - Aging
JID - 101508617
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Lipids)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism
MH  - Carcinoma, Hepatocellular/metabolism/*pathology
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Lipid Metabolism
MH  - Lipids/*biosynthesis
MH  - Liver Neoplasms/metabolism/*pathology
MH  - Non-alcoholic Fatty Liver Disease/*pathology
MH  - Oxygen/pharmacology
MH  - Phosphatidylinositol 3-Kinases/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/genetics/*metabolism
MH  - TOR Serine-Threonine Kinases/genetics/metabolism
MH  - Up-Regulation
PMC - PMC6932893
OTO - NOTNLM
OT  - HIF-2alpha
OT  - hepatocellular carcinoma
OT  - lipid metabolism
OT  - microenvironment
OT  - non-alcoholic fatty liver disease
COIS- CONFLICTS OF INTEREST: The authors have declared no conflicts of interest.
EDAT- 2019/12/05 06:00
MHDA- 2020/10/10 06:00
PMCR- 2019/12/15
CRDT- 2019/12/05 06:00
PHST- 2019/02/10 00:00 [received]
PHST- 2019/11/17 00:00 [accepted]
PHST- 2019/12/05 06:00 [pubmed]
PHST- 2020/10/10 06:00 [medline]
PHST- 2019/12/05 06:00 [entrez]
PHST- 2019/12/15 00:00 [pmc-release]
AID - 102488 [pii]
AID - 10.18632/aging.102488 [doi]
PST - ppublish
SO  - Aging (Albany NY). 2019 Dec 4;11(23):10839-10860. doi: 10.18632/aging.102488. 
      Epub 2019 Dec 4.