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)
Sources
Abstract
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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#1Xiaobin Guo (Peking Union Medical College)H-Index: 1
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Metastasis accounts for 90% of cancer death worldwide, and effective therapeutic strategies are lacking. The aim of this work is to identify the key drivers in tumor metastasis and screen therapeutics for treatment of esophageal squamous cell carcinoma (ESCC). Gene Ontology analysis of The Cancer Genome Atlas (TCGA) gene expression datasets of ESCC patients with or without lympy metastasis identifies that TGFβ2 is highly enriched in the pathways essential for tumor metastasis and upregulates in ...
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