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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number30217
JournalScientific Reports
Volume6
DOIs
StatePublished - 26 Jul 2016
Externally publishedYes

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