School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, China.
Cell Death Dis. 2017 Jul 13;8(7):e2924. doi: 10.1038/cddis.2017.311.
The acquisition of epithelial-mesenchymal transition (EMT) and/or existence of a sub-population of cancer stem-like cells (CSC) are associated with malignant behavior and chemoresistance. To identify which factor could promote EMT and CSC formation and uncover the mechanistic role of such factor is important for novel and targeted therapies. In the present study, we found that the long intergenic non-coding RNA linc-DYNC2H1-4 was upregulated in pancreatic cancer cell line BxPC-3-Gem with acquired gemcitabine resistance. Knockdown of linc-DYNC2H1-4 decreased the invasive behavior of BxPC-3-Gem cells while ectopic expression of linc-DYNC2H1-4 promoted the acquisition of EMT and stemness of the parental sensitive cells. Linc-DYNC2H1-4 upregulated ZEB1, the EMT key player, which led to upregulation and downregulation of its targets vimentin and E-cadherin respectively, as well as enhanced the expressions of CSC makers Lin28, Nanog, Sox2 and Oct4. Linc-DYNC2H1-4 is mainly located in the cytosol. Mechanically, it could sponge miR-145 that targets ZEB1, Lin28, Nanog, Sox2, Oct4 to restore these EMT and CSC-associated genes expressions. We proved that MMP3, the nearby gene of linc-DYNC2H1-4 in the sense strand, was also a target of miR-145. Downregulation of MMP3 by miR-145 was reverted by linc-DYNC2H1-4, indicating that competing with miR-145 is one of the mechanisms for linc-DYNC2H1-4 to regulate MMP3. In summary, our results explore the important role of linc-DYNC2H1-4 in the acquisition of EMT and CSC, and the impact it has on gemcitabine resistance in pancreatic cancer cells.
上皮间质转化 (EMT) 的获得和/或癌症干细胞样细胞 (CSC) 的存在与恶性行为和化疗耐药性有关。确定哪些因素可以促进 EMT 和 CSC 的形成，并揭示这种因素的机制作用，对于新的靶向治疗方法非常重要。在本研究中，我们发现长链非编码 RNA linc-DYNC2H1-4 在获得吉西他滨耐药性的胰腺癌细胞系 BxPC-3-Gem 中上调。linc-DYNC2H1-4 的敲低降低了 BxPC-3-Gem 细胞的侵袭行为，而 linc-DYNC2H1-4 的异位表达促进了亲本敏感细胞 EMT 的获得和干性。linc-DYNC2H1-4 上调 EMT 的关键调节因子 ZEB1，导致其靶标波形蛋白和 E-钙黏蛋白分别上调和下调，并增强了 CSC 标志物 Lin28、Nanog、Sox2 和 Oct4 的表达。linc-DYNC2H1-4 主要位于细胞质中。在机制上，它可以海绵状 miR-145，其靶向 ZEB1、Lin28、Nanog、Sox2、Oct4 以恢复这些 EMT 和 CSC 相关基因的表达。我们证明 sense 链上 linc-DYNC2H1-4 附近的基因 MMP3 也是 miR-145 的靶标。miR-145 下调 MMP3 被 linc-DYNC2H1-4 逆转，表明与 miR-145 竞争是 linc-DYNC2H1-4 调节 MMP3 的机制之一。总之，我们的研究结果探索了 linc-DYNC2H1-4 在 EMT 和 CSC 获得中的重要作用，以及它对胰腺癌细胞中吉西他滨耐药性的影响。
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