title: p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells.
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.
authors.affiliation: 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.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Umemura
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.affiliation: 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.
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: 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.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Yamachika
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Font-Burgada
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Departments of Bioengineering, Cellular and Molecular Medicine, and Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.affiliation: Departments of Bioengineering, Cellular and Molecular Medicine, and Chemistry and Biochemistry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Raghunandan
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Angeles
authors.initials: A
authors.lastname: Duran
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Linares
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Reina-Campos
authors.affiliation: 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.
authors.forename: Shiori
authors.initials: S
authors.lastname: Umemura
authors.affiliation: Department of Pathology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Valasek
authors.affiliation: 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.
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.affiliation: 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.
authors.forename: Kanji
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: 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.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford-Burnham-Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.affiliation: 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.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002470:Cell Survival; D004052:Diethylnitrosamine / Q000009:adverse effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D009374:Neoplasms, Experimental; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D000071456:Sequestosome-1 Protein / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D015854:Up-Regulation
chemical_list: C489427:MYC protein, human; D046912:Multiprotein Complexes; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D016271:Proto-Oncogene Proteins c-myc; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D004052:Diethylnitrosamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases