Research Papers:

Chemopreventive and chemotherapeutic effects of dietary supplementation of vitamin D on cholangiocarcinoma in a Chemical-Induced animal model

Kun-Chun Chiang, Chun-Nan Yeh, Kun-Ju Lin, Li-Jen Su, Tzu-Chen Yen, Jong-Hwei S. Pang, Atsushi Kittaka, Chi-Chin Sun, Miin-Fu Chen, Yi-Yin Jan, Tai C. Chen _, Horng-Heng Juang and Ta-Sen Yeh

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Oncotarget. 2014; 5:3849-3861. https://doi.org/10.18632/oncotarget.2000

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Kun-Chun Chiang1,*, Chun-Nan Yeh2,*, Kun-Ju Lin3, Li-Jen Su4, Tzu-Chen Yen3, Jong-Hwei S. Pang5, Atsushi Kittaka6, Chi-Chin Sun7, Miin-Fu Chen2, Yi-Yin Jan2, Tai C. Chen8, Horng-Heng Juang9 and Ta-Sen Yeh2

1 General Surgery Department, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC

2 General Surgery Department, Chang Gung Memorial Hospital, Linkoul, Taoyuan, Taiwan, ROC

3 Nuclear medicine department, Chang Gung Memorial Hospital, Linkoul, Taoyuan, Taiwan, ROC

4 Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taoyuan, Taiwan, ROC

5 Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, ROC

6 Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1Kaga, Itabashi, Tokyo, Japan

7 Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC

8 Boston University School of Medicine, Boston, MA, USA

9 Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C

* These Authors contributed equally to this work


Tai C. Chen, email:

Horng-Heng Juang, email:

Ta-SenYeh, email:

Keywords: cholangiocarcinoma; vitamin D; chemoprevention; LCN2; NGAL

Received: March 25, 2014 Accepted: May 20, 2014 Published: May 22, 2014


Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer. Vitamin D supplementation is getting popular due to its anti-tumor functions after conversion to its active form, 1α,25(OH)2D. 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 analogs against ICC are warranted.

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