DCLK1-Short Splice Variant Promotes Esophageal Squamous Cell Carcinoma Progression via the MAPK/ERK/MMP2 Pathway
DCLK1-Short Splice Variant Promotes Esophageal Squamous Cell Carcinoma Progression via the MAPK/ERK/MMP2 Pathway
复制标题
DCLK1-短剪接变异体通过 MAPK/ERK/MMP2 途径促进食管鳞状细胞癌进展
DOI：
10.1158/1541-7786.mcr-21-0161
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发表时间：
2021-12-01
影响因子：
5.2
通讯作者：
Yao, Jiannan
中科院分区：
文献类型：
--
作者：
Ge, Yang;Fan, Xiaona;Yao, Jiannan
肿瘤干细胞（CSC）标志物双皮质素样激酶1（DCLK 1）与胃肠道肿瘤的恶性程度密切相关，以DCLK 1为靶点的药物具有潜在的治疗价值。然而，DCLK 1-S（DCLK 1亚型4），DCLK 1的一种缩短的剪接变体，调节的分子途径仍然不清楚。我们发现DCLK 1-S在人食管鳞状细胞癌（ESCC）组织中表达显著增加，并与恶性进展和不良预后相关。功能研究表明，由CRISPR/Cas9介导的DCLK 1的沉默抑制了ESCC细胞的增殖、迁移和侵袭。相反，这些变化在DCLK 1-S拯救或过表达后大部分逆转。更重要的是，DCLK 1-S显著增强体内原发性肿瘤形成和转移性肺定植。癌症基因组图谱数据库和分子生物学分析表明，DCLK 1-S与ESCC患者的上皮-间质转化（EMT）过程密切相关。进一步的RNA测序和京都基因和基因组百科全书分析表明MAPK信号通路明显富集。我们的体外研究表明DCLK 1-S通过MAPK/ERK信号通路诱导ESCC细胞MMP 2的表达，从而激活EMT。此外，ERK 1/2阻断剂SCH 772984的施用减弱了DCLK 1-S诱导的增殖和迁移表型。总之，这些发现表明DCLK 1-S可能是MAPK/ERK/MMP 2通路介导的ESCC进展中的关键分子，并且它有可能作为生物标志物或治疗靶点来改善ESCC患者的预后。
Cancer stem cell (CSC) marker doublecortin-like kinase 1 (DCLK1) contributes greatly to the malignancy of gastrointestinal cancers, and DCLK1-targeted agents have potential therapeutic value. However, the molecular pathways regulated by DCLK1-S (DCLK1 isoform 4), a shortened splice variant of DCLK1, still remain obscure. Here we found that the expression of DCLK1-S is significantly increased in human esophageal squamous cell carcinoma (ESCC) tissues and associated with malignant progression and poor prognosis. Functional studies indicated that silencing total of DCLK1 mediated by CRISPR/Cas9 inhibited ESCC cell proliferation, migration, and invasion. Conversely, these changes were largely reversed after DCLK1-S rescue or overexpression. More importantly, DCLK1-S significantly enhanced primary tumor formation and metastatic lung colonization in vivo. The Cancer Genome Atlas database and molecular analysis showed that DCLK1-S was closely related to the epithelial-mesenchymal transition (EMT) process in patients with ESCC. Further RNA sequencing and Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that MAPK signaling pathway was significantly enriched. Our in vitro study proclaimed that DCLK1-S induced MMP2 expression in ESCC cells via MAPK/ERK signaling, leading to the activation of EMT. In addition, administration of ERK1/2 blocker SCH772984 attenuated the proliferative and migratory phenotype induced by DCLK1-S. In conclusion, these findings suggest that DCLK1-S may be a key molecule in MAPK/ERK/MMP2 pathway-mediated progression of ESCC, and that it has potential as a biomarker or therapeutic target to improve outcomes in patients with ESCC.