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MTOR inhibition affects Yap1-?-catenin-induced hepatoblastoma growth and development.

ABSTRACT: Hepatoblastoma (HB) is the most common pediatric liver malignancy. Around 80% of HB demonstrate simultaneous activation of ?-catenin and Yes-associated protein 1 (Yap1). The mechanism by which these signaling pathways contribute to HB pathogenesis remain obscure. Recently, mTORC1 activation was reported in human HB cells and in a murine HB model driven by ?-catenin and Yap1. Here, we directly investigate the therapeutic impact of mTOR inhibition following HB development in the Yap1-?-catenin model. HB were established by hydrodynamic tail vein injection of Sleeping Beauty transposase and plasmids coding for ?N90-?-catenin and S127A-Yap1. Five weeks after injection, when HB were evident, mice were randomized into Rapamycin diet-fed or basal-diet-fed groups for 5-weeks. Tumor growth was monitored via ultrasound imaging and mice in both groups were euthanized after 5-weeks for molecular analysis. Transcriptomic analysis showed a strong correlation in gene expression between HB in the Yap1-?-catenin model and HB patient cohorts. Rapamycin treatment decreased HB burden, almost normalizing liver weight to body weight ratio. Ultrasound imaging showed reduction in tumor growth over the duration of Rapamycin treatment as compared to controls. Majority of HB in the controls exhibited crowded fetal or embryonal histology, while remnant tumors in the experimental group showed well-differentiated fetal morphology. Immunohistochemistry confirmed inhibition of mTORC1 in the Rapamycin group. Thus, Rapamycin reduces HB in a clinically relevant model driven by ?-catenin and Yap1, supporting use of mTORC1 inhibitors in their therapy. We also show the utility of standard and 3D ultrasound imaging for monitoring liver tumors in mice.

SUBMITTER: Molina L

PROVIDER: S-EPMC6407673 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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mTOR inhibition affects Yap1-β-catenin-induced hepatoblastoma growth and development.

Molina Laura L Yang Hong H Adebayo Michael Adeola O AO Oertel Michael M Bell Aaron A Singh Sucha S Chen Xin X Tao Junyan J Monga Satdarshan P S SPS

Oncotarget 20190219 15

Hepatoblastoma (HB) is the most common pediatric liver malignancy. Around 80% of HB demonstrate simultaneous activation of β-catenin and Yes-associated protein 1 (Yap1). The mechanism by which these signaling pathways contribute to HB pathogenesis remain obscure. Recently, mTORC1 activation was reported in human HB cells and in a murine HB model driven by β-catenin and Yap1. Here, we directly investigate the therapeutic impact of mTOR inhibition following HB development in the Yap1-β-catenin mod ...[more]

PMID: 30863496

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Project description:Aberrant activation of ?-catenin and Yes-associated protein 1 (Yap1) signaling pathways have been associated with the development of multiple tumor types. Yap functions as a transcriptional coactivator by interacting with TEA domain DNA binding proteins. We investigated the interactions among these pathways during hepatic tumorigenesis.We used immunohistochemical analysis to determine expression of ?-catenin and Yap1 in liver cancer specimens collected from patients in Europe and the United States, consisting of 104 hepatocellular carcinoma, 62 intrahepatic cholangiocarcinoma, and 94 hepatoblastoma samples. We assessed ?-catenin and Yap1 signaling and interactions in hepatoblastoma cell lines ((HuH6, HepG2, HepT1, HC-AFW1, HepG2, and HC-AFW1); proteins were knocked down with small interfering RNAs, and effects on proliferation and cell death were measured. Sleeping beauty-mediated hydrodynamic transfection was used to overexpress constitutively active forms of ?-catenin (?N90/?-catenin) and Yap1 (YapS127A) in livers of mice; tissues were collected, and histological and immunohistochemical analyses were performed.We observed nuclear localization of ?-catenin and Yap1 in 79% of hepatoblastoma samples but not in most hepatocellular carcinoma or intrahepatic cholangiocarcinoma samples. Yap1 and ?-catenin coprecipitated in hepatoblastoma but not hepatocellular carcinoma cells. Small interfering RNA-mediated knockdown of Yap1 or ?-catenin in hepatoblastoma cells reduced proliferation in an additive manner. Knockdown of Yap1 reduced its ability to coactivate transcription with ?-catenin; ?-catenin inhibitors inactivated Yap1. Overexpression of constitutively active forms of Yap1 and ?-catenin in mouse liver led to rapid tumorigenesis, with 100% mortality by 11 weeks. Tumor cells expressed both proteins, and human hepatoblastoma cells expressed common targets of their 2 signaling pathways. Yap1 binding of TEA domain factors was required for tumorigenesis in mice.?-catenin and the transcriptional regulator Yap1 interact physically and are activated in most human hepatoblastoma tissues; overexpression of activated forms of these proteins in livers of mice leads to rapid tumor development. Further analysis of these mice will allow further studies of these pathways in hepatoblastoma pathogenesis and could lead to the identification of new therapeutic targets.

Dataset Information

MTOR inhibition affects Yap1-?-catenin-induced hepatoblastoma growth and development.

Publications

mTOR inhibition affects Yap1-β-catenin-induced hepatoblastoma growth and development.

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