Department of Gastroenterology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, No. 7 Weiwu Road, Zhengzhou, 450003, Henan, China.
Department of Pathology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, 450003, Henan, China.
Pflugers Arch. 2020 Aug;472(8):1041-1049. doi: 10.1007/s00424-020-02415-z. Epub 2020 Jun 12.
Doublecortin-like kinase 1 (DCLK1) is involved in tumorigenesis, tumor growth and metastasis, and epithelial-to-mesenchymal transition in many digestive tract tumors. It is reportedly highly expressed in Barrett's esophagus and esophageal adenocarcinoma, but its effects on the occurrence and progression of esophageal squamous cell carcinoma (ESCC) remain unclear. In this study, real-time PCR and western blot analysis confirmed significant upregulation of DCLK1 expression in human ESCC tissues and cell lines. CCK-8 assay showed that transfection with siRNA against DCLK1 (si-DCLK1) markedly inhibited cell proliferation and colony formation in the ESCC cell lines Eca109 and TE1. Transwell assay revealed that si-DCLK1 transfection inhibited the migratory and invasive capacities of Eca109 and TE1 cells. Moreover, si-DCLK1 increased the chemosensitivity of these cells to cisplatin, as indicated by inhibited cell viability and colony formation, and increased ROS and apoptosis in cisplatin-treated cells. Western blot assay revealed that expression of nuclear β-catenin and c-Myc was significantly increased in ESCC tissues and that si-DCLK1 markedly downregulated nuclear β-catenin and c-Myc in Eca109 cells. Treatment with lithium chloride, an activator of β-catenin signaling, partially abolished the si-DCLK1-induced inhibition of proliferation, migration, invasion, and chemoresistance of ESCC cells. These findings suggest that knockdown of DCLK1 may inhibit the progression of ESCC by regulating proliferation, migration, invasion, and chemosensitivity via suppressing the β-catenin/c-Myc pathway, supporting a promising therapeutic target against ESCC.
双皮质醇激酶 1（DCLK1）参与多种消化道肿瘤的发生、肿瘤生长和转移以及上皮间质转化。据报道，DCLK1 在巴雷特食管和食管腺癌中高度表达，但它对食管鳞状细胞癌（ESCC）的发生和发展的影响尚不清楚。在本研究中，实时 PCR 和 Western blot 分析证实 DCLK1 在人 ESCC 组织和细胞系中表达显著上调。CCK-8 检测表明，针对 DCLK1 的 siRNA（si-DCLK1）转染显著抑制 ESCC 细胞系 Eca109 和 TE1 中的细胞增殖和集落形成。Transwell 检测表明，si-DCLK1 转染抑制 Eca109 和 TE1 细胞的迁移和侵袭能力。此外，si-DCLK1 增加了这些细胞对顺铂的化疗敏感性，表现为抑制细胞活力和集落形成，并增加顺铂处理细胞中的 ROS 和凋亡。Western blot 检测表明，核β-catenin 和 c-Myc 的表达在 ESCC 组织中显著增加，而 si-DCLK1 显著下调 Eca109 细胞中的核β-catenin 和 c-Myc。β-catenin 信号激活剂氯化锂处理部分消除了 si-DCLK1 诱导的 ESCC 细胞增殖、迁移、侵袭和化疗耐药性的抑制。这些发现表明，通过抑制β-catenin/c-Myc 通路，敲低 DCLK1 可能通过调节增殖、迁移、侵袭和化疗敏感性来抑制 ESCC 的进展，为 ESCC 的治疗提供了有希望的靶点。
