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

Shanshan Zhang, Jingxiao Wang, Haichuan Wang, Lingling Fan, Biao Fan, Billy Zeng, Junyan Tao, Xiaolei Li, Li Che, Antonio Cigliano, Silvia Ribback, Frank Dombrowski, Bin Chen, Wenming Cong, Lixin Wei, Diego F Calvisi, Xin Chen

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)995-1006
Number of pages12
JournalAmerican Journal of Pathology
Issue number4
Publication statusPublished - Apr 2018


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