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

• DOI: 10.1038/srep30217
• Publication Date: 2016-07-26T09:25:25Z
• Authors: 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
• Keywords: Male; 0301 basic medicine; Membrane Glycoproteins; Mice, Transgenic; Vitamin D Deficiency; Article; 3. Good health; Wnt Proteins; Mice; 03 medical and health sciences; Liver Neoplasms, Experimental; Toll-Like Receptor 7; Transforming Growth Factor beta; Animals; Humans; Smad3 Protein; Vitamin D; Signal Transduction

AbstractDisruption 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.