p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer

被引：200

作者：

Duran, Angeles ^{[1
]}

Hernandez, Eloy D. ^{[1
]}

Reina-Campos, Miguel ^{[1
,2
]}

Castilla, Elias A. ^{[1
]}

Subramaniam, Shankar ^{[3
,4
,5
]}

Raghunandan, Sindhu ^{[3
,4
,5
]}

Roberts, Lewis R. ^{[6
]}

Kisseleva, Tatiana ^{[7
]}

Karin, Michael ^{[8
,9
]}

Diaz-Meco, Maria T. ^{[1
]}

Moscat, Jorge ^{[1
]}

机构：

[1] Sanford Burnham Prebys Med Discovery Inst, Canc Metab & Signaling Networks Program, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA

[2] Sanford Burnham Prebys Med Discovery Inst, Sanford Burnham Prebys Grad Sch Biomed Sci, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA

[3] UCSD Sch Med, Moores Canc Ctr, Dept Bioengn, La Jolla, CA 92093 USA

[4] UCSD Sch Med, Moores Canc Ctr, Dept Cellular & Mol Med, La Jolla, CA 92093 USA

[5] UCSD Sch Med, Moores Canc Ctr, Dept Chem & Biochem, La Jolla, CA 92093 USA

[6] Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, Rochester, MN 55905 USA

[7] UCSD Sch Med, Moores Canc Ctr, Dept Surg, La Jolla, CA 92093 USA

[8] UCSD Sch Med, Moores Canc Ctr, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA

[9] UCSD Sch Med, Moores Canc Ctr, Dept Pathol, Lab Gene Regulat & Signal Transduct, La Jolla, CA 92093 USA

来源：

CANCER CELL | 2016年 / 30卷 / 04期

关键词：

PANCREATIC DUCTAL ADENOCARCINOMA; HEPATOCELLULAR-CARCINOMA; NUCLEAR RECEPTOR; DIRECT REPEATS; P62; OBESITY; TUMORIGENESIS; ACTIVATION; PATHOGENESIS; INFLAMMATION;

D O I：

10.1016/j.ccell.2016.09.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：595 / 609

页数：15

共 41 条

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