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Cancer Cell. 2016 Jun 13;29(6):935-948. doi: 10.1016/j.ccell.2016.04.006. Epub 2016 May 19.

p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells.

Author information

1
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
2
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
3
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
4
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
5
Departments of Bioengineering, Cellular and Molecular Medicine, and Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
6
Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
7
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
8
Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
9
Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
10
Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
11
Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
12
Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: jmoscat@sbpdiscovery.org.
13
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. Electronic address: karinoffice@ucsd.edu.

Abstract

p62 is a ubiquitin-binding autophagy receptor and signaling protein that accumulates in premalignant liver diseases and most hepatocellular carcinomas (HCCs). Although p62 was proposed to participate in the formation of benign adenomas in autophagy-deficient livers, its role in HCC initiation was not explored. Here we show that p62 is necessary and sufficient for HCC induction in mice and that its high expression in non-tumor human liver predicts rapid HCC recurrence after curative ablation. High p62 expression is needed for activation of NRF2 and mTORC1, induction of c-Myc, and protection of HCC-initiating cells from oxidative stress-induced death.

PMID:
27211490
PMCID:
PMC4907799
DOI:
10.1016/j.ccell.2016.04.006
[Indexed for MEDLINE]
Free PMC Article

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