Journal
BIOCHEMICAL PHARMACOLOGY
Volume 203, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2022.115198
Keywords
HCC; Low glucose microenviroment; BORIS; GLUT4; Invasion; Benfluorex and Ritonavir
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Funding
- National Natural Science Foundation of China [81172372]
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This study revealed that activation of the AMPK alpha 2/ HNF4A/BORIS/GLUT4 signaling pathway in a low-glucose microenvironment can significantly promote the invasion and metastasis of HCC cells. HNF4A and GLUT4 may have important potential applications as prognostic or drug target molecules.
Increasing evidence has revealed that the invasion and metastasis of HCC are intimately related to the low -glucose microenvironment, but the intrinsic regulatory mechanism remains unclear. It has been well docu-mented that AMPK regulates the transcriptional expression of GLUT4 and its catalytic subunit AMPK alpha 2 can negatively regulate the downstream target molecule HNF4A. Meanwhile, BORIS (Brother of the Regulator of Imprinted Sites) is able to modulate the Warburg effect by regulating the splicing of pyruvate kinase M2 (PKM2), a critical enzyme in glycolysis. Through bioinformatic analysis and a series of overexpression, knockdown, and complementation experiments, we demonstrated that HNF4A can directly act on BORIS and negatively regulate its expression, thereby inhibiting hepatoma cell motility and tumor metastasis, whereas BORIS can directly act on GLUT4 and positively regulate its expression to enhance hepatoma cell motility and tumor metastasis. We also found that HNF4A agonist (Benfluorex) and GLUT4 inhibitor (antiviral drug Ritonavir) can suppress HCC cell proliferation and glucose uptake. Taken together, these results all suggest that activation of the AMPK alpha 2/ HNF4A/BORIS/GLUT4 signaling pathway in a low-glucose microenvironment can significantly promote the invasion and metastasis of HCC cells, while HNF4A and GLUT4 may have important potential applications as prognostic or drug target molecules.
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