Andrea Perra1, Marta Anna Kowalik1, Elena Ghiso2, Giovanna Maria Ledda-Columbano1, Luca Di Tommaso3, Maria Maddalena Angioni1, Carlotta Raschioni3, Elena Testore2, Massimo Roncalli3, Silvia Giordano4, Amedeo Columbano5. 1. Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy. 2. Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute - FPO, IRCCS, 10060 Candiolo (Torino), Italy. 3. University of Milano and Humanitas Clinical and Research Center, Rozzano, Milano, Italy. 4. Department of Oncology, University of Torino School of Medicine, Candiolo Cancer Institute - FPO, IRCCS, 10060 Candiolo (Torino), Italy. Electronic address: silvia.giordano@unito.it. 5. Department of Biomedical Sciences, Unit of Oncology and Molecular Pathology, University of Cagliari, Cagliari, Italy. Electronic address: columbano@unica.it.
Abstract
BACKGROUND & AIMS: Although the growth suppressing Hippo pathway has been implicated in hepatocellular carcinoma (HCC) pathogenesis, it is unknown at which stage of hepatocarcinogenesis its dysregulation occurs. We investigated in rat and human preneoplastic lesions whether overexpression of the transcriptional co-activator Yes-associated protein (YAP) is an early event. METHODS: The experimental model used is the resistant-hepatocyte (R-H) rat model. Gene expression was determined by qRT-PCR or immunohistochemistry. Forward genetic experiments were performed in human HCC cells and in murine oval cells. RESULTS: All foci of preneoplastic hepatocytes, generated in rats 4weeks after diethylnitrosamine (DENA) treatment, displayed YAP accumulation. This was associated with down-regulation of the β-TRCP ligase, known to mediate YAP degradation, and of microRNA-375, targeting YAP. YAP accumulation was paralleled by the up-regulation of its target genes. Increased YAP expression was also observed in human early dysplastic nodules and adenomas. Animal treatment with verteporfin (VP), which disrupts the formation of the YAP-TEAD complex, significantly reduced preneoplastic foci and oval cell proliferation. In vitro experiments confirmed that VP-mediated YAP inhibition impaired cell growth in HCC and oval cells; notably, oval cell transduction with wild type or active YAP conferred tumorigenic properties in vitro and in vivo. CONCLUSIONS: These results suggest that (i) YAP overexpression is an early event in rat and human liver tumourigenesis; (ii) it is critical for the clonal expansion of carcinogen-initiated hepatocytes and oval cells, and (iii) VP-induced disruption of the YAP-TEAD interaction may provide an important approach for the treatment of YAP-overexpressing cancers.
BACKGROUND & AIMS: Although the growth suppressing Hippo pathway has been implicated in hepatocellular carcinoma (HCC) pathogenesis, it is unknown at which stage of hepatocarcinogenesis its dysregulation occurs. We investigated in rat and human preneoplastic lesions whether overexpression of the transcriptional co-activator Yes-associated protein (YAP) is an early event. METHODS: The experimental model used is the resistant-hepatocyte (R-H) rat model. Gene expression was determined by qRT-PCR or immunohistochemistry. Forward genetic experiments were performed in human HCC cells and in murine oval cells. RESULTS: All foci of preneoplastic hepatocytes, generated in rats 4weeks after diethylnitrosamine (DENA) treatment, displayed YAP accumulation. This was associated with down-regulation of the β-TRCP ligase, known to mediate YAP degradation, and of microRNA-375, targeting YAP. YAP accumulation was paralleled by the up-regulation of its target genes. Increased YAP expression was also observed in human early dysplastic nodules and adenomas. Animal treatment with verteporfin (VP), which disrupts the formation of the YAP-TEAD complex, significantly reduced preneoplastic foci and oval cell proliferation. In vitro experiments confirmed that VP-mediated YAP inhibition impaired cell growth in HCC and oval cells; notably, oval cell transduction with wild type or active YAP conferred tumorigenic properties in vitro and in vivo. CONCLUSIONS: These results suggest that (i) YAP overexpression is an early event in rat and human liver tumourigenesis; (ii) it is critical for the clonal expansion of carcinogen-initiated hepatocytes and oval cells, and (iii) VP-induced disruption of the YAP-TEAD interaction may provide an important approach for the treatment of YAP-overexpressing cancers.
Authors: Sagar R Shah; Jayoung Kim; Paula Schiapparelli; Carla A Vazquez-Ramos; Juan C Martinez-Gutierrez; Alejandro Ruiz-Valls; Kyle Inman; James G Shamul; Jordan J Green; Alfredo Quinones-Hinojosa Journal: Mol Pharm Date: 2019-03-11 Impact factor: 4.939
Authors: Cecile Rouleau; Arun T Pores Fernando; Justin H Hwang; Nathalie Faure; Tao Jiang; Elizabeth A White; Thomas M Roberts; Brian S Schaffhausen Journal: J Virol Date: 2016-07-27 Impact factor: 5.103