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 MoscatMichael Karin

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

337 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 (US)
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
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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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

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

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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.",

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",

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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.

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ER -

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

Abstract

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