title: Chemopreventive and chemotherapeutic effect of dietary supplementation of vitamin D on cholangiocarcinoma in a Chemical-Induced animal model.
abstract: Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer. Vitamin D, a pro-hormone, is getting popular due to its hormone-like functions after converted to its active form, 1α,25(OH)2D3. Here, we show that dietary supplementation with 6 IU/g of vitamin D greatly suppressed ICC initiation and progression without apparent toxicity in a chemically induced rat model. Microarray analysis of rat ICC tissues showed vitamin D supplementation modulated the expressions of several unique genes, including lipocalin 2 (Lcn2), confirmed by RT-qPCR and immunohistochemical (IHC) staining. Further, 53 of 80 human ICC specimens (66%) exhibited high LCN2 expression and LCN2 knockdown in SNU308 cells decreased cell growth and migration, suggesting LCN2 be an oncogene in human ICC. As human ICC SNU1079 cells were treated by 1α,25(OH)2D3, LCN2 expression and cell proliferation were attenuated. The downregulation of LCN2 expression was blunted when vitamin D receptor (VDR) was knocked down, implicating that the in vivo Lcn2 downregulation is a direct consequence of vitamin D supplementation Our results support the prevailing concept that vitamin D status is negatively associated with cancer incidence and mortality and suggest LCN2 may be a potential target against ICC. Further studies of application of vitamin D or its analog against ICC are warranted.
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.forename: Kun-Ju
authors.initials: KJ
authors.lastname: Lin
authors.forename: Li-Jen
authors.initials: LJ
authors.lastname: Su
authors.forename: Tzu-Chen
authors.initials: TC
authors.lastname: Yen
authors.forename: Jong-Hwei S
authors.initials: JH
authors.lastname: Pang
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.forename: Chi-Chin
authors.initials: CC
authors.lastname: Sun
authors.forename: Miin-Fu
authors.initials: MF
authors.lastname: Chen
authors.forename: Yi-Yin
authors.initials: YY
authors.lastname: Jan
authors.affiliation: Boston University School of Medicine, Boston, MA, USA.
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C.
authors.forename: Horng-Heng
authors.initials: HH
authors.lastname: Juang
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Linkoul, Taoyuan, Taiwan, ROC.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
mesh_terms: D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001650:Bile Duct Neoplasms / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000097:blood; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018890:Chemoprevention; D018281:Cholangiocarcinoma / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D049268:Positron-Emission Tomography; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014807:Vitamin D / Q000008:administration & dosage*
chemical_list: D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; C097278:Lcn2 protein, rat; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D014807:Vitamin D; D002118:Calcium