title: MART-10 represses cholangiocarcinoma cell growth and high vitamin D receptor expression indicates better prognosis for cholangiocarcinoma.
abstract: Cholangiocarcinoma (CCA) is a devastating disease due to no effective treatments available. Since the non-mineral functions of vitamin D emerges, 1α,25(OH)2D3, the active form of vitamin D, has been applied in anti-cancer researches. In this study, we demonstrated that both the 1α,25(OH)2D3analog, MART-10, and 1α,25(OH)2D3possessed anti-growth effect on human CCA cells with MART-10 much more potent than 1α,25(OH)2D3. The growth inhibition of both drugs were mediated by induction of G0/G1 cell cycle arrest through upregulation of p27 and downregulation of CDK4, CDK6, and cyclin D3. Human neutrophil gelatinase associated lipocalin (NGAL) was found to be involved in 1α,25(OH)2D3and MART-10 meditated growth inhibition for CCA as knockdown of NGAL decreased Ki-67 expression in SNU308 cells and rendered SNU308 cells less responsive to 1α,25(OH)2D3and MART-10 treatment. Vitamin D receptor (VDR) knockdown partly abolished MART-10-induced inhibition of NGAL and cell growth in SNU308 cells. The xenograft animal study demonstrated MART-10 could effectively repressed CCA growth in vivo without inducing obvious side effects. The IHC examination of human CCA specimen for VDR revealed that higher VDR expression was linked with better prognosis. Collectively, our results suggest that MART-10 could be a promising regimen for CCA treatment.
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung, R.O.C, Taiwan.|Director of Zebrafish center of Keelung Chang Gung Memorial Hospital, R.O.C, Taiwan.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.affiliation: General Surgery Department and Liver research center, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan, R.O.C, Taiwan.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital, 222, Mai-Chin Road, Keelung, R.O.C, Taiwan.
authors.forename: Cheng-Cheng
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, R.O.C, Taiwan.
authors.forename: Yu-Chan
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, 333, R.O.C, Taiwan.
authors.forename: Horng-Heng
authors.initials: HH
authors.lastname: Juang
authors.affiliation: General Surgery Department and Liver research center, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan, R.O.C, Taiwan.
authors.forename: Chi-Tung
authors.initials: CT
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, R.O.C, Taiwan.
authors.forename: Jong-Hwei S
authors.initials: JS
authors.lastname: Pang
authors.affiliation: General Surgery Department and Liver research center, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan, R.O.C, Taiwan.
authors.forename: Jun-Te
authors.initials: JT
authors.lastname: Hsu
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa, 252-5195, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.affiliation: Boston University School of Medicine, M-1022, 715 Albany Street, Boston, MA 02118, USA.
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa, 252-5195, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, R.O.C, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: General Surgery Department and Liver research center, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan, R.O.C, Taiwan.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
mesh_terms: D000368:Aged; D000818:Animals; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D011379:Prognosis; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C569618:19-nor-2-(3-hydroxypropyl)-1,25-dihydroxyvitamin D3; D018167:Receptors, Calcitriol; D002762:Cholecalciferol