Abstract

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.

Highlights

  • Hepatoblastoma (HB) is the most common liver malignancy in children

  • As a first step to study the functional crosstalk between Yes-associated protein (YAP) and mammalian target of rapamycin complex 1 (mTORC1) in HB, we analyzed the protein levels of β-catenin, YAP, transcriptional co-activator with PDZ binding motif (TAZ), and members of the mammalian target of rapamycin (mTOR) pathway using two human HB cell lines, namely Hep293TT and HepG2 cells [18, 19]

  • We demonstrate that mTORC1 is activated in both human HB cell lines and mouse YAP/β-catenininduced tumor tissues

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Summary

Introduction

Hepatoblastoma (HB) is the most common liver malignancy in children. HB usually occurs in the first 3 years of life. The development of adjuvant, neo-adjuvant chemotherapy as well as the new surgical resection methods significantly improved the patients’ survival rate in the last decades [3]. Despite these significant achievements in HB treatment, the prognosis of patients with metastasis and those who are at a stage of pretreatment extent of disease (PRETEXT) IV remains unfavorable [4]. Novel targeted therapy strategies against HB are highly needed. To achieve this goal, a better characterization of the molecular genetics and signaling pathways underlying HB pathogenesis is imperative

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