Journal
CANCER CELL
Volume 30, Issue 4, Pages 595-609Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2016.09.004
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Funding
- NIH [R01DK108743, R01CA172025, R01CA192642, 5P30CA030199, R01CA163798, R01CA118165]
- Superfund Basic Research Program [P42ES010337]
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Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Vitamin D receptor (VDR) activation in HSCs inhibits liver inflammation and fibrosis. We found that p62/SQSTM1, a protein upregulated in liver parenchymal cells but downregulated in HCC-associated HSCs, negatively controls HSC activation. Total body or HSC-specific p62 ablation potentiates HSCs and enhances inflammation, fibrosis, and HCC progression. p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target gene recruitment. Loss of p62 in HSCs impairs the repression of fibrosis and inflammation by VDR agonists. This demonstrates that p62 is a negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling in HSCs, whose activation supports HCC.
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