Chiang Kun-Chun, Yeh Chun-Nan, Lin Kun-Ju, Su Li-Jen, Yen Tzu-Chen, Pang Jong-Hwei S, Kittaka Atsushi, Sun Chi-Chin, Chen Miin-Fu, Jan Yi-Yin, Chen Tai C, Juang Horng-Heng, Yeh Ta-Sen
General Surgery Department, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC.
Boston University School of Medicine, Boston, MA, USA.
Oncotarget. 2014 Jun 15;5(11):3849-61. doi: 10.18632/oncotarget.2000.
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.
肝内胆管癌（ICC）是一种侵袭性癌症。维生素D作为一种激素原，在转化为其活性形式1α,25(OH)2D3后，因其类似激素的功能而日益受到关注。在此，我们表明，在化学诱导的大鼠模型中，以6 IU/g的剂量进行维生素D膳食补充可显著抑制ICC的起始和进展，且无明显毒性。对大鼠ICC组织进行的微阵列分析表明，补充维生素D可调节包括脂质运载蛋白2（Lcn2）在内的多个独特基因的表达，这一结果通过逆转录定量聚合酶链反应（RT-qPCR）和免疫组织化学（IHC）染色得到证实。此外，80例人类ICC标本中有53例（66%）表现出高LCN2表达，而在SNU308细胞中敲低LCN2可降低细胞生长和迁移，这表明LCN2是人类ICC中的一种癌基因。当用人ICC SNU1079细胞进行1α,25(OH)2D3处理时，LCN2表达和细胞增殖均减弱。当维生素D受体（VDR）被敲低时，LCN2表达的下调受到抑制，这意味着体内Lcn2的下调是补充维生素D的直接结果。我们的结果支持了维生素D状态与癌症发病率和死亡率呈负相关的普遍观点，并表明LCN2可能是针对ICC的一个潜在靶点。有必要对维生素D或其类似物在ICC治疗中的应用进行进一步研究。
