Abstract
Disruption of the TGF-β pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-β signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3+/− mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-β pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-β pathway member expression levels and β-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-β member expression with lower β-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-β pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and β-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.
Highlights
Immunomodulatory activities, supporting a role in cancer prevention and treatment trials[1,4]
Vitamin D (VD) deficiency has been observed in cirrhosis and liver cancer patients[18], we examined the role of VD in liver tumor formation in a TGF-βpathway inactivated mouse model
High dietary VD/VD-deficient doses did not affect the number of lung adenocarcinomas in either Smad3+/− or wild type mice (Fig. 1c, Supplementary Table S1), and we did not observe a noticeable increase in total tumor burden in the lung at the time the data was collected, suggesting VD levels on tumorigenesis appear to be restricted to the liver
Summary
Immunomodulatory activities, supporting a role in cancer prevention and treatment trials[1,4]. The TGF-βsignaling pathway is aberrant in fibrosis as well as in liver and gastrointestinal cancers, with a complex context-dependent role, promoting epithelial mesenchymal transition (EMT), to suppressing and prompting oncogenesis. It is often considered a driving pathway for these specific tumors. Our results indicate that the markedly high tumor burden in Smad[3] mutant mice results from aberrant Toll-like receptor (TLR) expression as well as Wnt signaling, and demonstrate functional regulation of TLR7 through Smad[3]. Our studies suggest that in specific patient populations with disruption of TGF-βsignaling, low VD markers correlate with activation of the Wnt pathway and a high risk of tumorigenesis
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