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ABSTRACT: Objectives
The relative contributions of inflammatory signalling and sequential oncogenic dysregulation driving liver cancer pathogenesis remain incompletely understood. Lymphotoxin-? receptor (LT?R) signalling is critically involved in hepatitis and liver tumorigenesis. Therefore, we explored the interdependence of inflammatory lymphotoxin signalling and specific oncogenic pathways in the progression of hepatic cancer.Design
Pathologically distinct liver tumours were initiated by hydrodynamic transfection of oncogenic V-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT)/?-catenin or AKT/Notch expressing plasmids. To investigate the relationship of LT?R signalling and specific oncogenic pathways, LT?R antagonist (LT?R-Fc) or agonist (anti-LT?R) were administered post oncogene transfection. Initiated livers/tumours were investigated for changes in oncogene expression, tumour proliferation, progression, latency and pathology. Moreover, specific LT?R-mediated molecular events were investigated in human liver cancer cell lines and through transcriptional analyses of samples from patients with intrahepatic cholangiocarcinoma (ICC).Results
AKT/?-catenin-transfected livers displayed increased expression of LT? and LT?R, with antagonism of LT?R signalling reducing tumour progression and enhancing survival. Conversely, enforced LT?R-activation of AKT/?-catenin-initiated tumours induced robust increases in proliferation and progression of hepatic tumour phenotypes in an AKT-dependent manner. LT?R-activation also rapidly accelerated ICC progression initiated by AKT/Notch, but not Notch alone. Moreover, LT?R-accelerated development coincides with increases of Notch, Hes1, c-MYC, pAKT and ?-catenin. We further demonstrate LT?R signalling in human liver cancer cell lines to be a regulator of Notch, pAKTser473 and ?-catenin. Transcriptome analysis of samples from patients with ICC links increased LT?R network expression with poor patient survival, increased Notch1 expression and Notch and AKT/PI3K signalling.Conclusions
Our findings link LT?R and oncogenic AKT signalling in the development of ICC.
SUBMITTER: Scarzello AJ
PROVIDER: S-EPMC5036232 | biostudies-literature | 2016 Oct
REPOSITORIES: biostudies-literature
Gut 20150723 10
<h4>Objectives</h4>The relative contributions of inflammatory signalling and sequential oncogenic dysregulation driving liver cancer pathogenesis remain incompletely understood. Lymphotoxin-β receptor (LTβR) signalling is critically involved in hepatitis and liver tumorigenesis. Therefore, we explored the interdependence of inflammatory lymphotoxin signalling and specific oncogenic pathways in the progression of hepatic cancer.<h4>Design</h4>Pathologically distinct liver tumours were initiated b ...[more]