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
N1 - Funding Information:
We thank E.P. Sandgren and K.L. Guan for MUP-uPA and Tsc1 F/F mice, respectively, X. Xiao for the AAV vector, H. Nakai and A. Miyanohara for advice and AAV generation, R. Loomba, D.E. Kleiner, T. Kisseleva, and D.A. Brenner for suggestions and constructive criticism, Karin laboratory members for helpful discussions, and Cell Signaling Technology, Santa Cruz Biotechnology, and Abcam for antibodies. A.U., H.N., K.Y., and Y.I. were supported by JSPS KAKENHI Grant ( #15H06547 , A.U.; #15K19313 , H.N.; #25461005 , K.Y.; #15K09018 , Y.I.), the Kanae Foundation for the Promotion of Medical Science (A.U., H.N.), and a Global Grant Scholarship from The Rotary Foundation (A.U.), the Japanese Society of Gastroenterology (H.N.), and Research Program on Hepatitis from the Japan Agency for Medical Research and Development , AMED (H.N., K.K.). K.T., J.F.-B., and Z.Z. were supported by Postdoctoral Fellowship for Research Abroad, Research Fellowship for Young Scientists from the JSPS , and a Uehara Memorial Foundation Fellowship (K.T.); CIRM Training Grant II (TG2-01154; J.F.-B.) and Cancer Research Institute (CRI) Irvington postdoctoral fellowship (Z.Z.). M.K. holds the Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases. Research was supported by the NIH ( R01CA163798 , R01CA118165 , and P01DK098108 to M.K.; R01CA172025 and R01DK108743 to J.M.; R01CA192642 to M.T.D.-M.; 5P30CA030199 to M.T.D.-M. and J.M.), the Superfund Basic Research Program ( P42ES010337 to M.K. and E.S.), and the American Association for Study of Liver Diseases/American Liver Foundation (E.S.).
Publisher Copyright:
© 2016 Elsevier Inc.
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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U2 - 10.1016/j.ccell.2016.04.006
DO - 10.1016/j.ccell.2016.04.006
M3 - Article
C2 - 27211490
AN - SCOPUS:84975468197
SN - 1535-6108
VL - 29
SP - 935
EP - 948
JO - Cancer Cell
JF - Cancer Cell
IS - 6
ER -