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

Atsushi Umemura; Feng He; Koji Taniguchi; Hayato Nakagawa; Shinichiro Yamachika; Joan Font-Burgada; Zhenyu Zhong; Shankar Subramaniam; Sindhu Raghunandan; Angeles Duran; Juan F. Linares; Miguel Reina-Campos; Shiori Umemura; Mark A. Valasek; Ekihiro Seki; Kanji Yamaguchi; Kazuhiko Koike; Yoshito Itoh; Maria T. Diaz-Meco; Jorge Moscat; Michael Karin

doi:10.1016/j.ccell.2016.04.006

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

Atsushi Umemura
, Feng He
, Koji Taniguchi
, Hayato Nakagawa
, Shinichiro Yamachika
, Joan Font-Burgada
, Zhenyu Zhong
, Shankar Subramaniam
, Sindhu Raghunandan
, Angeles Duran
, Juan F. Linares
, Miguel Reina-Campos
, Shiori Umemura
, Mark A. Valasek
, Ekihiro Seki
, Kanji Yamaguchi
, Kazuhiko Koike
, Yoshito Itoh
, Maria T. Diaz-Meco
, Jorge Moscat

Michael Karin

University of California at San Diego
Kyoto Prefectural University of Medicine
Kyushu University
Keio University
The University of Tokyo
Sanford Burnham Prebys Medical Discovery Institute
Cedars-Sinai Medical Center

Research output: Contribution to journal › Article › peer-review

423 Scopus citations

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.

Original language	English
Pages (from-to)	935-948
Number of pages	14
Journal	Cancer Cell
Volume	29
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2016.04.006
State	Published - Jun 13 2016

Keywords

Animals
Carcinoma, Hepatocellular/genetics
Cell Survival
Diethylnitrosamine/adverse effects
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms/genetics
Mechanistic Target of Rapamycin Complex 1
Mice
Mice, Transgenic
Multiprotein Complexes/genetics
NF-E2-Related Factor 2/genetics
Neoplasms, Experimental
Neoplastic Stem Cells/cytology
Proto-Oncogene Proteins c-myc/genetics
Sequestosome-1 Protein/genetics
TOR Serine-Threonine Kinases/genetics
Up-Regulation

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10.1016/j.ccell.2016.04.006

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Umemura, A., He, F., Taniguchi, K., Nakagawa, H., Yamachika, S., Font-Burgada, J., Zhong, Z., Subramaniam, S., Raghunandan, S., Duran, A., Linares, J. F., Reina-Campos, M., Umemura, S., Valasek, M. A., Seki, E., Yamaguchi, K., Koike, K., Itoh, Y., Diaz-Meco, M. T., ... Karin, M. (2016). p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells. Cancer Cell, 29(6), 935-948. https://doi.org/10.1016/j.ccell.2016.04.006

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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.",

keywords = "Animals, Carcinoma, Hepatocellular/genetics, Cell Survival, Diethylnitrosamine/adverse effects, Gene Expression Regulation, Neoplastic, Humans, Liver Neoplasms/genetics, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Transgenic, Multiprotein Complexes/genetics, NF-E2-Related Factor 2/genetics, Neoplasms, Experimental, Neoplastic Stem Cells/cytology, Proto-Oncogene Proteins c-myc/genetics, Sequestosome-1 Protein/genetics, TOR Serine-Threonine Kinases/genetics, Up-Regulation",

author = "Atsushi Umemura and Feng He and Koji Taniguchi and Hayato Nakagawa and Shinichiro Yamachika and Joan Font-Burgada and Zhenyu Zhong and Shankar Subramaniam and Sindhu Raghunandan and Angeles Duran and Linares, \{Juan F.\} and Miguel Reina-Campos and Shiori Umemura and Valasek, \{Mark A.\} and Ekihiro Seki and Kanji Yamaguchi and Kazuhiko Koike and Yoshito Itoh and Diaz-Meco, \{Maria T.\} and Jorge Moscat and Michael Karin",

year = "2016",

month = jun,

day = "13",

doi = "10.1016/j.ccell.2016.04.006",

language = "English",

volume = "29",

pages = "935--948",

journal = "Cancer Cell",

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Umemura, A, He, F, Taniguchi, K, Nakagawa, H, Yamachika, S, Font-Burgada, J, Zhong, Z, Subramaniam, S, Raghunandan, S, Duran, A, Linares, JF, Reina-Campos, M, Umemura, S, Valasek, MA, Seki, E, Yamaguchi, K, Koike, K, Itoh, Y, Diaz-Meco, MT, Moscat, J & Karin, M 2016, 'p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells', Cancer Cell, vol. 29, no. 6, pp. 935-948. https://doi.org/10.1016/j.ccell.2016.04.006

TY - JOUR

T1 - p62, Upregulated during Preneoplasia, Induces Hepatocellular Carcinogenesis by Maintaining Survival of Stressed HCC-Initiating Cells

AU - Umemura, Atsushi

AU - He, Feng

AU - Taniguchi, Koji

AU - Nakagawa, Hayato

AU - Yamachika, Shinichiro

AU - Font-Burgada, Joan

AU - Zhong, Zhenyu

AU - Subramaniam, Shankar

AU - Raghunandan, Sindhu

AU - Duran, Angeles

AU - Linares, Juan F.

AU - Reina-Campos, Miguel

AU - Umemura, Shiori

AU - Valasek, Mark A.

AU - Seki, Ekihiro

AU - Yamaguchi, Kanji

AU - Koike, Kazuhiko

AU - Itoh, Yoshito

AU - Diaz-Meco, Maria T.

AU - Moscat, Jorge

AU - Karin, Michael

PY - 2016/6/13

Y1 - 2016/6/13

N2 - 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.

AB - 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.

KW - Animals

KW - Carcinoma, Hepatocellular/genetics

KW - Cell Survival

KW - Diethylnitrosamine/adverse effects

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Liver Neoplasms/genetics

KW - Mechanistic Target of Rapamycin Complex 1

KW - Mice

KW - Mice, Transgenic

KW - Multiprotein Complexes/genetics

KW - NF-E2-Related Factor 2/genetics

KW - Neoplasms, Experimental

KW - Neoplastic Stem Cells/cytology

KW - Proto-Oncogene Proteins c-myc/genetics

KW - Sequestosome-1 Protein/genetics

KW - TOR Serine-Threonine Kinases/genetics

KW - Up-Regulation

UR - https://www.scopus.com/pages/publications/84975468197

U2 - 10.1016/j.ccell.2016.04.006

DO - 10.1016/j.ccell.2016.04.006

M3 - Article

C2 - 27211490

SN - 1535-6108

VL - 29

SP - 935

EP - 948

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

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Keywords

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