title: Co-activation of PIK3CA and Yap promotes development of hepatocellular and cholangiocellular tumors in mouse and human liver.
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.
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.|Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, U.S.A.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, U.S.A.|School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Tao
authors.affiliation: Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany.
authors.forename: Antonio
authors.initials: A
authors.lastname: Cigliano
authors.affiliation: Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany.
authors.forename: Marcella
authors.initials: M
authors.lastname: Sini
authors.affiliation: Department of Pathology, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.|Inserm, U1162, Génomique Fonctionnelle des Tumeurs Solides, Institut Universitaire d'Hematologie, Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.affiliation: Department of Digestive and Hepatobiliairy Surgery, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Henri Mondor, Créteil, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Azoulay
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, U.S.A.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, U.S.A.
authors.forename: Lijie
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Evert
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Demartis
authors.affiliation: Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ribback
authors.affiliation: Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Utpatel
authors.affiliation: Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.affiliation: Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Evert
authors.affiliation: Institute of Pathology, University Medicine of Greifswald, Greifswald, Germany.|Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, U.S.A.|School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, Hubei, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C486223:Yap1 protein, mouse; C484760:PIK3CA protein, human; C546639:Pik3ca protein, mouse
keywords: HCC; Hippo; PI3K; cholangiocarcinoma; liver tumor
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