Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling

Debanjan Dhar; Laura Antonucci; Hayato Nakagawa; Ju Youn Kim; Elisabeth Glitzner; Stefano Caruso; Shabnam Shalapour; Ling Yang; Mark A Valasek; Sooyeon Lee; Kerstin Minnich; Ekihiro Seki; Jan Tuckermann; Maria Sibilia; Jessica Zucman-Rossi; Michael Karin

doi:10.1016/j.ccell.2018.05.003

Liver Cancer Initiation Requires p53 Inhibition by CD44-Enhanced Growth Factor Signaling

Cancer Cell. 2018 Jun 11;33(6):1061-1077.e6. doi: 10.1016/j.ccell.2018.05.003.

Authors

Affiliations

¹ Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA.
² Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
³ Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
⁴ Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs Solides, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, 75010 Paris, France.
⁵ Department of Medicine, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
⁶ Department of Pathology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA.
⁷ Institute for Comparative Molecular Endocrinology (CME), University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany.
⁸ Leibniz Institute of Age Research-Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
⁹ Department of Medicine, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Medicine, Cedars-Sinai, 8700 Beverly Boulevard, Davis Building, Los Angeles, CA 90048, USA.
¹⁰ Institute for Comparative Molecular Endocrinology (CME), University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany; Leibniz Institute of Age Research-Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany.
¹¹ Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Pathology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Moores Cancer Center, University of California San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0723, USA. Electronic address: karinoffice@ucsd.edu.

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.

Keywords: CD44; DNA damage response; EGFR; HCC; MDM2 nuclear translocation; cancer initiation; hepatocellular carcinoma; liver cancer; p53; p53 termination.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Animals
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Cells, Cultured
DNA Damage
Female
Gene Expression Regulation, Neoplastic
Hepatocytes / metabolism
Humans
Hyaluronan Receptors / genetics*
Hyaluronan Receptors / metabolism
Liver Neoplasms / genetics*
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Male
Mice, Inbred C57BL
Mice, Knockout
Middle Aged
Signal Transduction / genetics
Tumor Suppressor Protein p53 / genetics*
Tumor Suppressor Protein p53 / metabolism

Substances

Hyaluronan Receptors
Tumor Suppressor Protein p53

Abstract

Publication types

MeSH terms

Substances

Grants and funding