title: 1, 25(OH)₂D₃ inhibits hepatocellular carcinoma development through reducing secretion of inflammatory cytokines from immunocytes.
abstract: 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 p27(kip1) 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 p27(kip1) gene dependent way. Collectively, 1,25(OH)₂D₃ inhibits HCC development through up-regulating the expression of p27(kip1) in immune cell and reducing inflammatory cytokine production.
authors.affiliation: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, China. qyma56@mail.xjtu.edu.cn.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Ma
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Ma
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhou
authors.forename: Lulu
authors.initials: L
authors.lastname: Chen
authors.forename: Shuang
authors.initials: S
authors.lastname: Zhou
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
authors.forename: Erxi
authors.initials: E
authors.lastname: Wu
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol