DCLK1-Short Splice Variant Promotes Esophageal Squamous Cell Carcinoma Progression Via the MAPK/ERK/MMP2 Pathway

Published on Oct 5, 2021in Molecular Cancer Research5.852
· DOI :10.1158/1541-7786.MCR-21-0161
Yang Ge8
Estimated H-index: 8
(Capital Medical University),
Xiaona Fan (Beijing Chao-Yang Hospital)+ 7 AuthorsJiannan Yao6
Estimated H-index: 6
(Capital Medical University)
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. TCGA (The Cancer Genome Atlas) database and molecular analysis showed that DCLK1-S was closely related to the epithelial-mesenchymal transition (EMT) process in ESCC patients. Further RNA-seq and KEGG analysis demonstrated that MAPK signaling pathway was significantly enriched. Our invitro study proclaimed that DCLK1-S induced MMP2 expression in ESCC cells via MAPK/ERK signaling, leading to the activation of EMT. Additionally, 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 ESCC patients. Implications: DCLK1-S induces ESCC progression by activating the MAPK/ERK/MMP2 axis and may serve as a prognostic biomarker or therapeutic target for ESCC patients.
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