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FoxA2 inhibits the proliferation of hepatic progenitor cells by reducing PI3K/Akt/HK2‐mediated glycolysis
Author(s) -
Wang Ping,
Cong Min,
Liu Tianhui,
Li Yaqiong,
Liu Lin,
Sun Shujie,
Sun Liying,
Zhu Zhijun,
Ma Hong,
You Hong,
Zhang Haiyan,
Jia Jidong
Publication year - 2020
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.29759
Subject(s) - foxa2 , protein kinase b , pi3k/akt/mtor pathway , anaerobic glycolysis , microbiology and biotechnology , cell growth , biology , gene knockdown , chemistry , glycolysis , transcription factor , cancer research , signal transduction , biochemistry , apoptosis , gene , metabolism
Abstract FoxA2 is an essential transcription factor for liver organogenesis and homeostasis. Although reduced expression of FoxA2 has been associated with chronic liver diseases, hepatic progenitor cells (HPCs) that are activated in these circumstances express FoxA2. However, the functional effects and underlying mechanism of FoxA2 in HPCs are still unknown. As revealed by immunostaining, HPCs expressed FoxA2 in human cirrhotic livers and in the livers of choline‐deficient diet supplemented with ethionine (CDE) rats. Knocking down FoxA2 in HPCs isolated from CDE rats significantly increased cell proliferation and aerobic glycolysis. Moreover, gene transcription, protein expression, and the enzyme activities of hexokinase 2 (HK2) were upregulated, and blocking HK2 activities via 2‐deoxyglucose markedly reduced cell proliferation and aerobic glycolysis. Kyoto Encyclopedia of Genes and Genomes analysis revealed that FoxA2 knockdown enhanced the transcription of genes involved in the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (Akt) pathway and triggered downstream Akt phosphorylation. Blocking the PI3K/Akt pathway by Ly294002 inhibited HK2 activities, aerobic glycolysis, and cell proliferation in FoxA2‐knockdown cells. Therefore, FoxA2 plays an important role in the proliferation and inhibition of HPCs by suppressing PI3K/Akt/HK2‐regulated aerobic glycolysis.