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Article Publish Status: FREE
Abstract Title:

Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor-β/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation.

Abstract Source:

Sci Rep. 2016 ;6:30217. Epub 2016 Jul 26. PMID: 27456065

Abstract Author(s):

Jian Chen, Lior H Katz, Nina M Muñoz, Shoujun Gu, Ji-Hyun Shin, Wilma S Jogunoori, Mi-Hye Lee, Mitchell D Belkin, Sang-Bae Kim, Jon C White, Jaclyn Andricovich, Alexandros Tzatsos, Shulin Li, Sang Soo Kim, Kirti Shetty, Bibhuti Mishra, Asif Rashid, Ju-Seog Lee, Lopa Mishra

Article Affiliation:

Jian Chen

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 withlower 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.

Study Type : Animal Study

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