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

被引：393

作者：

Umemura, Atsushi ^{[1
,7
]}

He, Feng ^{[1
]}

Taniguchi, Koji ^{[1
,12
,13
]}

Nakagawa, Hayato ^{[1
,9
]}

Yamachika, Shinichiro ^{[1
]}

Font-Burgada, Joan ^{[1
]}

Zhong, Zhenyu ^{[1
]}

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

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

Duran, Angeles ^{[11
]}

Linares, Juan F. ^{[11
]}

Reina-Campos, Miguel ^{[11
]}

Umemura, Shiori ^{[1
,8
]}

Valasek, Mark A. ^{[2
]}

Seki, Ekihiro ^{[6
,10
]}

Yamaguchi, Kanji ^{[7
]}

Koike, Kazuhiko ^{[9
]}

Itoh, Yoshito ^{[7
]}

Diaz-Meco, Maria T. ^{[11
]}

Moscat, Jorge ^{[11
]}

Karin, Michael ^{[1
,2
]}

机构：

[1] Univ Calif San Diego, Dept Pharmacol, Lab Gene Regulat & Signal Transduct, 9500 Gilman Dr, La Jolla, CA 92093 USA

[2] Univ Calif San Diego, Dept Pathol, 9500 Gilman Dr, La Jolla, CA 92093 USA

[3] Univ Calif San Diego, Dept Bioengn, 9500 Gilman Dr, La Jolla, CA 92093 USA

[4] Univ Calif San Diego, Dept Cellular & Mol Med, 9500 Gilman Dr, La Jolla, CA 92093 USA

[5] Univ Calif San Diego, Dept Chem & Biochem, 9500 Gilman Dr, La Jolla, CA 92093 USA

[6] Univ Calif San Diego, Dept Med, 9500 Gilman Dr, La Jolla, CA 92093 USA

[7] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Mol Gastroenterol & Hepatol, Kamigyo Ku, 465 Kajii Cho, Kyoto 6028566, Japan

[8] Kyoto Prefectural Univ Med, Grad Sch Med Sci, Dept Obstet & Gynecol, Kamigyo Ku, 465 Kajii Cho, Kyoto 6028566, Japan

[9] Univ Tokyo, Grad Sch Med, Dept Gastroenterol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan

[10] Cedars Sinai Med Ctr, Dept Med, Div Gastroenterol, 8700 Beverly Blvd, Los Angeles, CA 90048 USA

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

[12] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka 8128582, Japan

[13] Keio Univ, Sch Med, Dept Microbiol & Immunol, Tokyo 1608582, Japan

来源：

CANCER CELL | 2016年 / 29卷 / 06期

关键词：

LIVER-CANCER; NONALCOHOLIC STEATOHEPATITIS; COMPENSATORY PROLIFERATION; NRF2; ACTIVATION; CARCINOMA; AUTOPHAGY; TUMORIGENESIS; INFLAMMATION; MUTATIONS;

D O I：

10.1016/j.ccell.2016.04.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：935 / 948

页数：14

共 67 条

[1] Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy [J].

Chandler, Randy J. ;

LaFave, Matthew C. ;

Varshney, Gaurav K. ;

Trivedi, Niraj S. ;

Carrillo-Carrasco, Nuria ;

Senac, Julien S. ;

Wu, Weiwei ;

Hoffmann, Victoria ;

Elkahloun, Abdel G. ;

Burgess, Shawn M. ;

Venditti, Charles P. .

JOURNAL OF CLINICAL INVESTIGATION, 2015, 125 (02) :870-880

[2] Functions of Autophagy in Hepatic and Pancreatic Physiology and Disease [J].

Czaja, Mark J. .

GASTROENTEROLOGY, 2011, 140 (07) :1895-1908

[3] NRF2 regulates serine biosynthesis in non-small cell lung cancer [J].

DeNicola, Gina M. ;

Chen, Pei-Hsuan ;

Mullarky, Edouard ;

Sudderth, Jessica A. ;

Hu, Zeping ;

Wu, David ;

Tang, Hao ;

Xie, Yang ;

Asara, John M. ;

Huffman, Kenneth E. ;

Wistuba, Ignacio I. ;

Minna, John D. ;

DeBerardinis, Ralph J. ;

Cantley, Lewis C. .

NATURE GENETICS, 2015, 47 (12) :1475-+

[4] Are the Mallory bodies and intracellular hyaline bodies in neoplastic and non-neoplastic hepatocytes related? [J].

Denk, H ;

Stumptner, C ;

Fuchsbichler, A ;

Müller, T ;

Farr, GH ;

Müller, W ;

Terracciano, L ;

Zatlouka, K .

JOURNAL OF PATHOLOGY, 2006, 208 (05) :653-661

[5] p62 Is a Key Regulator of Nutrient Sensing in the mTORC1 Pathway [J].

Duran, Angeles ;

Amanchy, Ramars ;

Linares, Juan F. ;

Joshi, Jayashree ;

Abu-Baker, Shadi ;

Porollo, Aleksey ;

Hansen, Malene ;

Moscat, Jorge ;

Diaz-Meco, Maria T. .

MOLECULAR CELL, 2011, 44 (01) :134-146

[6] CURRENT CONCEPTS Hepatocellular Carcinoma [J].

El-Serag, Hashem B. .

NEW ENGLAND JOURNAL OF MEDICINE, 2011, 365 (12) :1118-1127

[7] CLONAL ADAPTATION DURING CARCINOGENESIS [J].

FARBER, E .

BIOCHEMICAL PHARMACOLOGY, 1990, 39 (12) :1837-1846

[8] Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma [J].

Finkin, Shlomi ;

Yuan, Detian ;

Stein, Ilan ;

Taniguchi, Koji ;

Weber, Achim ;

Unger, Kristian ;

Browning, Jeffrey L. ;

Goossens, Nicolas ;

Nakagawa, Shigeki ;

Gunasekaran, Ganesh ;

Schwartz, Myron E. ;

Kobayashi, Masahiro ;

Kumada, Hiromitsu ;

Berger, Michael ;

Pappo, Orit ;

Rajewsky, Klaus ;

Hoshida, Yujin ;

Karin, Michael ;

Heikenwalder, Mathias ;

Ben-Neriah, Yinon ;

Pikarsky, Eli .

NATURE IMMUNOLOGY, 2015, 16 (12) :1235-1244

[9] Hybrid Periportal Hepatocytes Regenerate the Injured Liver without Giving Rise to Cancer [J].

Font-Burgada, Joan ;

Shalapour, Shabnam ;

Ramaswamy, Suvasini ;

Hsueh, Brian ;

Rossell, David ;

Umemura, Atsushi ;

Taniguchi, Koji ;

Nakagawa, Hayato ;

Valasek, Mark A. ;

Ye, Li ;

Kopp, Janel L. ;

Sander, Maike ;

Carter, Hannah ;

Deisseroth, Karl ;

Verma, Inder M. ;

Karin, Michael .

CELL, 2015, 162 (04) :766-779

[10] Immunity, Inflammation, and Cancer [J].

Grivennikov, Sergei I. ;

Greten, Florian R. ;

Karin, Michael .

CELL, 2010, 140 (06) :883-899

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