Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor-β/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation.
Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor-β/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation.
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DOI：
10.1038/srep30217
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发表时间：
2016-07-26
影响因子：
4.6
通讯作者：
Mishra L
中科院分区：
文献类型：
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作者：
Chen J;Katz LH;Muñoz NM;Gu S;Shin JH;Jogunoori WS;Lee MH;Belkin MD;Kim SB;White JC;Andricovich J;Tzatsos A;Li S;Kim SS;Shetty K;Mishra B;Rashid A;Lee JS;Mishra L
TGF-β 途径的破坏与肝纤维化和肝脏肿瘤发生的抑制有关，这些病症与维生素 D (VD) 水平低相关。然而，在 TGF-β 信号传导背景下，VD 对肝肿瘤进展的潜在贡献仍有待探索。我们对肝肿瘤形成体内模型中的 VD 剥夺 (VDD) 的分析显示，与对照组相比，Smad3+/- 小鼠的肿瘤负荷显着增加了三倍，其中 TLR7 表达增加了三倍。 ChIP 和转录测定证实 Smad3 在两个 TLR7 启动子 SBE 位点结合。 TGF-β 途径和 VDD 之间的分子相互作用经过临床验证，其中缺乏 VD 补充与纤维化/肝硬化人肝组织中 TGF-β 途径成员表达水平低和 β-连环蛋白激活相关。随后补充 VD 导致 TGF-β 成员表达恢复，β-连环蛋白水平降低。生物信息学分析提供了 VD 相关基因的体细胞突变与 TGF-β 通路之间的正相关性。我们得出结论，在 Smad3 破坏的情况下，VDD 可能通过调节 TLR7 表达和 β-catenin 激活来促进肿瘤生长。因此，在 Smad3 信号传导异常的情况下，VD 可能是预防肝癌的有力候选者。
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.