Chiang Kun-Chun, Yeh Chun-Nan, Pang Jong-Hwei S, Hsu Jun-Te, Yeh Ta-Sen, Chen Li-Wei, Kuo Sheng-Fong, Takano Masashi, Chen Tai C, Kittaka Atsushi, Hsieh Po-Jen, Juang Horng-Heng
General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, R.O.C.
Zebrafish Center, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, R.O.C.
Anticancer Res. 2017 Nov;37(11):6215-6221. doi: 10.21873/anticanres.12072.
Pancreatic neuroendocrine tumors (PanNETs) are usually diagnosed in an advanced stage. Most patients with PanNETs die of metastasis. Vascular endothelial growth factor-A (VEGF-A) is a strong stimulator of angiogenesis and tumor metastasis. We aimed to investigate the effect of MART-10 [19-nor-2α-(3-hydroxypropyl)-1α,25(OH)D], a 1α,25-dihydroxy-vitamin D3 (1α,25(OH)D) analog, on PanNET cell metastasis after VEGF-A stimulation.
Migration and invasion assays, western blot, and immunofluorescent staining were applied in this study.
VEGF-A increased PanNET cell migration and invasion, which was attenuated by 1α,25(OH)D and MART-10. VEGF-A treatment stimulated epithelial-mesenchymal transition (EMT) of PanNET cells. During this process, expression of snail family transcriptional repressor 1 and 2, and fibronectin was up-regulated. 1α,25(OH)D and MART-10 counteracted VEGF-A-induced EMT. In addition, expression of neuropilin 1, a key protein in VEGF-A signaling, was down-regulated by 1α,25(OH)D and MART-10. Furthermore, synthesis of F-actin was increased by VEGF-A and reduced by 1α,25(OH)D and MART-10.
Our data indicate that MART-10 could be deemed a promising drug for PanNET treatment.
胰腺神经内分泌肿瘤（PanNETs）通常在晚期被诊断出来。大多数PanNETs患者死于转移。血管内皮生长因子-A（VEGF-A）是血管生成和肿瘤转移的强烈刺激因子。我们旨在研究1α,25-二羟基维生素D3（1α,25(OH)D）类似物MART-10[19-去甲-2α-(3-羟丙基)-1α,25(OH)D]对VEGF-A刺激后PanNET细胞转移的影响。
本研究采用迁移和侵袭实验、蛋白质印迹法及免疫荧光染色法。
VEGF-A增加了PanNET细胞的迁移和侵袭，而1α,25(OH)D和MART-10可减弱这种作用。VEGF-A处理刺激了PanNET细胞的上皮-间质转化（EMT）。在此过程中，蜗牛家族转录抑制因子1和2以及纤连蛋白的表达上调。1α,25(OH)D和MART-10可对抗VEGF-A诱导的EMT。此外，1α,25(OH)D和MART-10下调了VEGF-A信号通路中的关键蛋白神经纤毛蛋白1的表达。此外，VEGF-A增加了F-肌动蛋白的合成，而1α,25(OH)D和MART-10则减少了这种合成。
我们的数据表明，MART-10可被视为一种有前景的PanNET治疗药物。
