title: 25(OH)D Is Effective to Repress Human Cholangiocarcinoma Cell Growth through the Conversion of 25(OH)D to 1α,25(OH)₂D₃.
abstract: Cholangiocarcinoma (CCA) is a devastating disease without effective treatments. 1α,25(OH)₂D₃, the active form of Vitamin D, has emerged as a new anti-cancer regimen. However, the side effect of hypercalcemia impedes its systemic administration. 25(OH)D is biologically inert and needs hydroxylation by CYP27B1 to form 1α,25(OH)₂D₃, which is originally believed to only take place in kidneys. Recently, the extra-renal expression of CYP27B1 has been identified and in vitro conversion of 25(OH)D to 1α,25(OH)₂D₃ has been found in some cancer cells with CYP27B1 expression. In this study, CYP27B1 expression was demonstrated in CCA cells and human CCA specimens. 25(OH)D effectively represses SNU308 cells growth, which was strengthened or attenuated as CYP27B1 overexpression or knockdown. Lipocalcin-2 (LCN2) was also found to be repressed by 25(OH)D. After treatment with 800 ng/mL 25(OH)D, the intracellular 1α,25(OH)₂D₃ concentration was higher in SNU308 cells with CYP27B1 overexpression than wild type SNU308 cells. In a xenograft animal experiment, 25(OH)D, at a dose of 6 μg/kg or 20 μg/kg, significantly inhibited SNU308 cells' growth without inducing obvious side effects. Collectively, our results indicated that SNU308 cells were able to convert 25(OH)D to 1α,25(OH)₂D₃ and 25(OH)D CYP27B1 gene therapy could be deemed as a promising therapeutic direction for CCA.
authors.affiliation: General Surgery Department and Zebrafish Center, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan. robertviolet6292@yahoo.com.tw.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 244, Taiwan. yehchunnan@gmail.com.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.affiliation: Pathology Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan. rrooyyaall@yahoo.com.
authors.forename: Cheng-Cheng
authors.initials: CC
authors.lastname: Huang
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 244, Taiwan. tsy471027@adm.cgmh.org.tw.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 244, Taiwan. jonghwei@mail.cgu.edu.tw.
authors.forename: Jong-Hwei
authors.initials: JH
authors.lastname: S Pang
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 244, Taiwan. hsujt2813@adm.cgmh.org.tw.
authors.forename: Jun-Te
authors.initials: JT
authors.lastname: Hsu
authors.affiliation: Department of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan. leiwei@adm.cgmh.org.tw.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan. shengfoung@gmail.com.
authors.forename: Sheng-Fong
authors.initials: SF
authors.lastname: Kuo
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan. akittaka@pharm.teikyo-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.affiliation: Endocrine core lab, boston University School of Medicine, Boston, MA 02118, USA. taichen@bu.edu.
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 244, Taiwan. hhj143@mail.cgu.edu.tw.
authors.forename: Horng-Heng
authors.initials: HH
authors.lastname: Juang
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000818:Animals; D002117:Calcitriol / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D014807:Vitamin D; C104450:25-hydroxyvitamin D; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol
keywords: 1α-OHase; 25(OH)D; CYP27B1; cholangiocarcinoma; vitamin D