Oncotarget

Research Papers:

Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver

Xiaolei Li, Junyan Tao, Antonio Cigliano, Marcella Sini, Julien Calderaro, Daniel Azoulay, Chunmei Wang, Yan Liu, Lijie Jiang, Katja Evert, Maria I. Demartis, Silvia Ribback, Kirsten Utpatel, Frank Dombrowski, Matthias Evert, Diego F. Calvisi and Xin Chen _

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Oncotarget. 2015; 6:10102-10115. https://doi.org/10.18632/oncotarget.3546

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Abstract

Xiaolei Li1,2, Junyan Tao2,3, Antonio Cigliano4, Marcella Sini4, Julien Calderaro5,6, Daniel Azoulay7, Chunmei Wang2, Yan Liu1, Lijie Jiang2, Katja Evert4, Maria I. Demartis8, Silvia Ribback4, Kirsten Utpatel4, Frank Dombrowski4, Matthias Evert4, Diego F. Calvisi4,8 and Xin Chen2,3

1 Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi, P.R. China

2 Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, U.S.A

3 School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China

4 Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany

5 Department of Pathology, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, Créteil, France

6 Inserm, U1162, Génomique Fonctionnelle des Tumeurs Solides, Institut Universitaire d’Hematologie, Paris, France

7 Department of Digestive and Hepatobiliairy Surgery, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, Créteil, France

8 Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy

Correspondence to:

Diego F. Calvisi, email:

Xin Chen, email:

Keywords: HCC, cholangiocarcinoma, liver tumor, PI3K, hippo

Received: January 12, 2015 Accepted: February 13, 2015 Published: March 12, 2015

Abstract

Activation of the PI3K and Yes-associated protein (Yap) signaling pathways has been independently reported in human hepatocellular carcinoma (HCC). However, the oncogenic interactions between these two cascades in hepatocarcinogenesis remain undetermined. To assess the consequences of the crosstalk between the PI3K and Yap pathways along liver carcinogenesis, we generated a mouse model characterized by combined overexpression of activated mutant forms of PIK3CA (PIK3CAH1047R) and Yap (YapS127A) in the mouse liver using hydrodynamic transfection (PIK3CA/Yap). In addition, suppression of PI3K and Yap pathways was conducted in human HCC and cholangiocarcinoma (CCA) cell lines. We found that concomitant activation of PI3K and Yap pathways triggered rapid liver tumor development in mice. Histologically, tumors were pure HCC, CCA, or mixed HCC/CCA. At the molecular level, PIK3CA/Yap tumors were characterized by activation of the mTORC1/2, ERK/MAPK, and Notch pathways. Simultaneous activation of PI3K and Yap pathways frequently occurred in human liver tumor specimens and their combined suppression was highly detrimental for the growth of HCC and CCA cell lines. In conclusion, our study demonstrates the oncogenic cooperation between PI3K and Yap pathways along liver carcinogenesis. The PIK3CA/Yap mouse represents an important preclinical liver tumor model for the development of novel therapeutics against this malignancy.


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