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Am J Pathol. 2018 Apr;188(4):995-1006. doi: 10.1016/j.ajpath.2017.12.017. Epub 2018 Jan 31.

Hippo Cascade Controls Lineage Commitment of Liver Tumors in Mice and Humans.

Author information

1
Tumor Immunology and Gene Therapy Center, Second Military Medical University, Shanghai, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
2
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Second Clinical Medical School, Beijing University of Chinese Medicine, Beijing, China.
3
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Liver Transplantation Division, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
4
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California.
5
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California; Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital & Institute, Beijing, China.
6
Department of Pediatrics, University of California, San Francisco, California; Institute for Computational Health Sciences, University of California, San Francisco, California.
7
National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Italy.
8
Institute of Pathology, University of Greifswald, Greifswald, Germany.
9
Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
10
Tumor Immunology and Gene Therapy Center, Second Military Medical University, Shanghai, China.
11
Institute of Pathology, University of Greifswald, Greifswald, Germany. Electronic address: diego.calvisi@uni-greifswald.de.
12
Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, California. Electronic address: xin.chen@ucsf.edu.

Abstract

Primary liver cancer consists mainly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). A subset of human HCCs expresses a ICC-like gene signature and is classified as ICC-like HCC. The Hippo pathway is a critical regulator of normal and malignant liver development. However, the precise function(s) of the Hippo cascade along liver carcinogenesis remain to be fully delineated. The role of the Hippo pathway in a murine mixed HCC/ICC model induced by activated forms of AKT and Ras oncogenes (AKT/Ras) was investigated. The authors demonstrated the inactivation of Hippo in AKT/Ras liver tumors leading to nuclear localization of Yap and TAZ. Coexpression of AKT/Ras with Lats2, which activates Hippo, or the dominant negative form of TEAD2 (dnTEAD2), which blocks Yap/TAZ activity, resulted in delayed hepatocarcinogenesis and elimination of ICC-like lesions in the liver. Mechanistically, Notch2 expression was found to be down-regulated by the Hippo pathway in liver tumors. Overexpression of Lats2 or dnTEAD2 in human HCC cell lines inhibited their growth and led to the decreased expression of ICC-like markers, as well as Notch2 expression. Altogether, this study supports the key role of the Hippo cascade in regulating the differentiation status of liver tumors.

PMID:
29378174
PMCID:
PMC5866106
[Available on 2019-04-01]
DOI:
10.1016/j.ajpath.2017.12.017

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