@article{a9e6264780ce4e0f94205f6cf4b4ec5b,
title = "Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling",
abstract = "How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to escape p53-induced death and senescence and respond to proliferative signals that promote fixation of mutations and their transmission to daughter cells that go on to become HCC progenitors. Dhar et al. show that CD44 expression induced in carcinogen-exposed hepatocytes potentiates AKT signaling to activate Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to respond to proliferative signals, leading their daughter cells to become HCC progenitors.",
keywords = "CD44, DNA damage response, EGFR, HCC, MDM2 nuclear translocation, cancer initiation, hepatocellular carcinoma, liver cancer, p53, p53 termination",
author = "Debanjan Dhar and Laura Antonucci and Hayato Nakagawa and Kim, {Ju Youn} and Elisabeth Glitzner and Stefano Caruso and Shabnam Shalapour and Ling Yang and Valasek, {Mark A.} and Sooyeon Lee and Kerstin Minnich and Ekihiro Seki and Jan Tuckermann and Maria Sibilia and Jessica Zucman-Rossi and Michael Karin",
note = "Funding Information: Research was supported by the Superfund Basic Research Program ( P42ES010337 ) to M.K. and E.S., NIH ( R01-CA118165 ) grant to M.K. D.D was supported by the ALF Liver scholar award and a Young Investigator Award from the CureSearch Foundation; S.S. by the fellowship from CRI-Irvington and PCF Young Investigator Award; L.A. by the iCARE Fellowship, AIRC (Associazione Italiana per la ricerca sul cancro) co-founded by the European Union ; J.Y.K. by the AACR-Bayer HCC post-doctoral fellowship; H.N. by the JSPS KAKENHI Grant Number 15K19313 , Japanese Society of Gastroenterology , and Astelas Foundation for Research on Metabolic Disorders; and L.Y. by the National Natural Science Foundation of China ( 30500658 , 81370550 and 81570530 ). S.L. and K.M. were supported by intramural grants from the FLI . J.T. was supported by the Boehringer Ingelheim Stiftung . Generation of Cd44-Floxed mice was supported by DFG grant He-551 to Peter Herrlich. We are grateful to Dr. Zhao-Qi Wang for advice in ES cell targeting and Dr. Milen Kirilov for providing targeting vectors and advice in the targeting strategy. M.S. was supported by the European Research Council (ERC) Advanced Grant 694883 and Austrian Science Fund special research program SFB F3518-B20 . J.Z.R. was supported by the Ligue Nationale contre le Cancer (Equipe Labellis{\'e}e), Labex OncoImmunology (investissement d'avenir), Coup d{\textquoteright}Elan de la Fondation Bettencourt-Shueller , the SIRIC CARPEM , and Fondation M{\'e}rieux . We thank Souradipta Ganguly for help with experiments. Funding Information: Research was supported by the Superfund Basic Research Program (P42ES010337) to M.K. and E.S., NIH (R01-CA118165) grant to M.K. D.D was supported by the ALF Liver scholar award and a Young Investigator Award from the CureSearch Foundation; S.S. by the fellowship from CRI-Irvington and PCF Young Investigator Award; L.A. by the iCARE Fellowship, AIRC (Associazione Italiana per la ricerca sul cancro) co-founded by the European Union; J.Y.K. by the AACR-Bayer HCC post-doctoral fellowship; H.N. by the JSPS KAKENHI Grant Number 15K19313, Japanese Society of Gastroenterology, and Astelas Foundation for Research on Metabolic Disorders; and L.Y. by the National Natural Science Foundation of China (30500658, 81370550 and 81570530). S.L. and K.M. were supported by intramural grants from the FLI. J.T. was supported by the Boehringer Ingelheim Stiftung. Generation of Cd44-Floxed mice was supported by DFG grant He-551 to Peter Herrlich. We are grateful to Dr. Zhao-Qi Wang for advice in ES cell targeting and Dr. Milen Kirilov for providing targeting vectors and advice in the targeting strategy. M.S. was supported by the European Research Council (ERC) Advanced Grant 694883 and Austrian Science Fund special research program SFB F3518-B20. J.Z.R. was supported by the Ligue Nationale contre le Cancer (Equipe Labellis{\'e}e), Labex OncoImmunology (investissement d'avenir), Coup d'Elan de la Fondation Bettencourt-Shueller, the SIRIC CARPEM, and Fondation M{\'e}rieux. We thank Souradipta Ganguly for help with experiments. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jun,
day = "11",
doi = "10.1016/j.ccell.2018.05.003",
language = "English (US)",
volume = "33",
pages = "1061--1077.e6",
journal = "Cancer cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "6",
}