Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1
Pancreatic Neuroendocrine Tumors and EMT Behavior Are Driven by the CSC Marker DCLK1
复制标题
DOI：
10.1158/1541-7786.mcr-16-0285
复制
发表时间：
2017-06-01
影响因子：
5.2
通讯作者：
Torimura, Takuji
中科院分区：
文献类型：
--
作者：
Ikezono, Yu;Koga, Hironori;Torimura, Takuji
双皮质素样激酶1 （DCLK1）是肠道和胰腺癌干细胞的标志物，在神经母细胞瘤中高度表达。本研究旨在评估DCLK1在胰腺神经内分泌肿瘤（PNET）组织中的表达水平，并探讨该分子在多例PNET患者、细胞（BON1、QGP1和CM）和肿瘤异种移植物的临床组织中的作用。免疫组织化学结果显示，所有PNET组织中DCLK1作为全长亚型高度和弥漫性表达，与原发性肝脏NETs中检测到的相同。dclk1过表达的PNET细胞系（QGP1-DCLK1）表现出上皮-间质转化（EMT）相关的基因特征，并通过实时PCR和免疫印迹验证了Slug （SNAI2）、N-Cadherin （CDH2）和Vimentin （VIM）的显著上调。在伤口愈合实验中，QGP1-DCLK1细胞增加了细胞迁移，并在裸鼠中形成了更大的异种移植肿瘤。参与快速生长肿瘤形成的因子包括p-FAK（位于Tyr925上）、p-ERK1/2、p-AKT、Paxillin和Cyclin D1，当DCLK1被敲除或药理学抑制时，这些分子的表达被消除。总之，DCLK1在人类PNET组织标本和细胞中首次得到了稳健和普遍的表达。DCLK1表征PNET细胞行为，诱导p-FAK/ slug介导的EMT。这些发现提示了通过靶向DCLK1开发针对PNETs的新治疗策略的可能性。(c) 2017 aacr。
Doublecortin-like kinase 1 (DCLK1), a marker for intestinal and pancreatic cancer stem cells, is highly expressed in neuroblastomas. This study was conducted to assess DCLK1 expression levels in pancreatic neuroendocrine tumor (PNET) tissues and to explore the roles of this molecule in clinical tissue from multiple PNET patients, cells (BON1, QGP1, and CM) and tumor xenografts. Immunohistochemically, all PNET tissues highly and diffusely expressed DCLK1 as a full-length isoform, identical to that detected in primary liver NETs. A DCLK1-overexpressing PNET cell line (QGP1-DCLK1) exhibited epithelial-mesenchymal transition (EMT)-related gene signatures, and robust upregulation of Slug (SNAI2), N-Cadherin (CDH2), and Vimentin (VIM) was validated by real-time PCR and immunoblotting. QGP1-DCLK1 cells had increased cell migration in a wound-healing assay and formed significantly larger xenograft tumors in nude mice. The factors involved in the formation of the fast-growing tumors included p-FAK (on Tyr925), p-ERK1/2, p-AKT, Paxillin, and Cyclin D1, which upon knockdown or pharmacologic inhibition of DCLK1 abolished the expression of these molecules. In conclusion, robust and ubiquitous expression of DCLK1 was first demonstrated here in human PNET tissue specimens and cells. DCLK1 characterized the PNET cell behavior, inducing p-FAK/SLUG-mediated EMT. These findings suggest the possibility of developing novel therapeutic strategies against PNETs by targeting DCLK1. (C) 2017 AACR.