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

作者：Chen Jian; Katz Lior H; Munoz Nina M; Gu Shoujun; Shin Ji hyun; Jogunoori Wilma S; Lee Mi Hye; Belkin Mitchell D; Kim Sang Bae; White Jon C; Andricovich Jaclyn; Tzatsos Alexandros; Li Shulin; Kim Sang Soo; Shetty Kirti; Mishra Bibhuti; Rashid Asif; Lee Ju Seog; Mishra Lopa^*

来源：Scientific Reports, 2016, 6(1): 30217.

DOI：10.1038/srep30217

Disruption of the TGF-beta 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-beta 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-beta pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-beta pathway member expression levels and beta-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-beta member expression with lower beta-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-beta pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and beta-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling.

• 出版日期2016-7-26