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Int. J. Mol. Sci. 2016, 17(8), 1326; doi:10.3390/ijms17081326

25(OH)D Is Effective to Repress Human Cholangiocarcinoma Cell Growth through the Conversion of 25(OH)D to 1α,25(OH)2D3

1
General Surgery Department and Zebrafish Center, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan
2
General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 244, Taiwan
3
Pathology Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan
4
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 244, Taiwan
5
Department of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan
6
Department of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chang Gung University, Keelung 204, Taiwan
7
Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
8
Endocrine core lab, boston University School of Medicine, Boston, MA 02118, USA
9
Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan 244, Taiwan
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Gregor Drummen
Received: 16 July 2016 / Revised: 4 August 2016 / Accepted: 9 August 2016 / Published: 12 August 2016
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
View Full-Text   |   Download PDF [7966 KB, uploaded 12 August 2016]   |  

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. View Full-Text
Keywords: cholangiocarcinoma; 25(OH)D; CYP27B1; 1α-OHase; vitamin D cholangiocarcinoma; 25(OH)D; CYP27B1; 1α-OHase; vitamin D
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Chiang, K.-C.; Yeh, C.-N.; Huang, C.-C.; Yeh, T.-S.; S. Pang, J.-H.; Hsu, J.-T.; Chen, L.-W.; Kuo, S.-F.; Kittaka, A.; Chen, T.C.; Juang, H.-H. 25(OH)D Is Effective to Repress Human Cholangiocarcinoma Cell Growth through the Conversion of 25(OH)D to 1α,25(OH)2D3. Int. J. Mol. Sci. 2016, 17, 1326.

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