Priority Research Papers:
Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development
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Pin Liu1,2, Diego F. Calvisi3, Andras Kiss4, Antonio Cigliano3, Zsuzsa Schaff4, Li Che2, Silvia Ribback3, Frank Dombrowski3, Dongchi Zhao1 and Xin Chen2
1 Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
2 Department of Bioengineering and Therapeutic Sciences, Liver Center, University of California San Francisco, San Francisco, CA, USA
3 Institute of Pathology, University of Greifswald, Greifswald, Germany
4 Second Department of Pathology, Semmelweis University, Budapest, Hungary
Xin Chen, email:
Dongchi Zhao, email:
Keywords: YAP/TAZ, mTORC1, SLC38A1, hepatoblastoma
Received: July 02, 2017 Accepted: August 21, 2017 Published: September 01, 2017
Hepatoblastoma (HB) is the most common type of liver malignancy in children. Recent studies suggest that activation of Yes-associated protein (YAP) is a major molecular event in HB development, as activated YAP synergizes with mutant β-catenin to promote HB formation in mice (YAP/β-catenin). However, how YAP regulates HB development remains poorly defined. Similarly, de-regulation of mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated in multiple tumor types, but its functional role in HB development is scarcely understood. In the present study, we found that mTORC1 is activated in human HB cells and YAP/β-catenin-induced mouse HB tumor tissues. mTOR inhibitor MLN0128 significantly inhibits human HB cell growth in vitro. Furthermore, ablation of Raptor, the unique subunit of mTORC1, strongly delayed YAP/β-catenin-induced HB development in mice. At the molecular level, we found that expression of the amino acid transporter SLC38A1 is induced in mouse HB tissues, and amino acid deprivation leads to mTORC1 suppression in HB cell lines. Silencing of YAP and/or its paralog, transcriptional co-activator with PDZ binding motif (TAZ), decreased SLC38A1 expression as well as mTORC1 activation in HB cells. Furthermore, a frequent and concomitant upregulation of mTORC1 and SLC38A1 was detected in a collection of human HB specimens. Altogether, our study demonstrates the key role of mTORC1 in HB development. YAP and TAZ promote HB development via inducing SLC38A1 expression, whose upregulation leads to mTORC1 activation. Targeting mTOR pathway or amino acid transporters may represent novel therapeutic strategies for the treatment of human HB.
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