期刊
CANCER CELL
卷 33, 期 6, 页码 1061-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2018.05.003
关键词
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资金
- Superfund Basic Research Program [P42ES010337]
- NIH [R01-CA118165]
- ALF Liver scholar award
- Young Investigator Award from CureSearch Foundation
- CRI-Irvington
- PCF Young Investigator Award
- iCARE Fellowship
- AIRC (Associazione Italiana per la ricerca sul cancro) - European Union
- AACR-Bayer HCC post-doctoral fellowship
- JSPS KAKENHI Grant [15K19313]
- Japanese Society of Gastroenterology
- Astelas Foundation for Research on Metabolic Disorders
- National Natural Science Foundation of China [30500658, 81370550, 81570530]
- FLI
- Boehringer Ingelheim Stiftung
- DFG [He-551]
- European Research Council (ERC) [694883]
- Austrian Science Fund special research program [SFB F3518-B20]
- Ligue Nationale contre le Cancer (Equipe Labellisee)
- Labex OncoImmunology (investissement d'avenir)
- Coup d'Elan de la Fondation Bettencourt-Shueller
- SIRIC CARPEM
- Fondation Merieux
- Grants-in-Aid for Scientific Research [15K19313] Funding Source: KAKEN
- European Research Council (ERC) [694883] Funding Source: European Research Council (ERC)
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.
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