Epidemiological and clinical studies have indicated that low vitamin D activity is not only associated with an
increased cancer risk and a more aggressive tumor growth, but also connected with an aggravated liver damage caused by
chronic inflammation. Meanwhile, increasing evidence has demonstrated that 1,25(OH)2D3 (the most biologically active
metabolite of vitamin D) can inhibit inflammatory response in some chronic inflammatory associated cancer, which is
considered to have the anti-tumor potency. However, the interaction between 1,25(OH)2D3 and inflammation during hepatocellular
carcinoma (HCC) initiation and progression is not yet clear. Here, we report an anti-tumorigenesis effect of
1,25(OH)2D3 via decreasing inflammatory cytokine secretion in HCC and hypothesize the possible underlying mechanism.
Firstly, we show that the enhanced tumor growth is associated with elevated inflammatory cytokine IL-6 and TNF-α
in 1α(OH)ase gene-knockout mice. Secondly, 1,25(OH)2D3 can inhibit vitamin D receptor (VDR) shRNA interfered tumor
cell growth through decreasing inflammatory cytokine secretion in vitro and in vivo. Finally, using p27kip1 gene
knock-out mouse model, we demonstrate that the effect of 1,25(OH)2D3 in inhibiting immune cell related inflammatory
cytokine secretion, exerts in a p27kip1 gene dependent way. Collectively, 1,25(OH)2D3 inhibits HCC development
through up-regulating the expression of p27kip1 in immune cell and reducing inflammatory cytokine production.
Keywords: HCC, chronic inflammation, 1, 25(OH)2D3, 1α(OH)ase, gene knockout, IL-6, TNF-α, STAT3 signaling , p27kip1, coculture.
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