Abstract
Despite recent advancements, the 5 year survival of head and neck squamous cell carcinoma (HNSCC) hovers at 60%. DCLK1 has been shown to regulate epithelial-to-mesenchymal transition as well as serving as a cancer stem cell marker in colon, pancreatic and renal cancer. Although it was reported that DCLK1 is associated with poor prognosis in oropharyngeal cancers, very little is known about the molecular characterization of DCLK1 in HNSCC. In this study, we performed a comprehensive transcriptome-based computational analysis on hundreds of HNSCC patients from TCGA and GEO databases, and found that DCLK1 expression positively correlates with NOTCH signaling pathway activation. Since NOTCH signaling has a recognized role in HNSCC tumorigenesis, we next performed a series of in vitro experiments in a collection of HNSCC cell lines to investigate the role of DCLK1 in NOTCH pathway regulation. Our analyses revealed that DCLK1 inhibition, using either a pharmacological inhibitor or siRNA, resulted in substantially decreased proliferation, invasion, migration, and colony formation. Furthermore, these effects paralleled downregulation of active NOTCH1, and its downstream effectors, HEY1, HES1 and HES5, whereas overexpression of DCLK1 in normal keratinocytes, lead to an upregulation of NOTCH signaling associated with increased proliferation. Analysis of 233 primary and 40 recurrent HNSCC cancer biopsies revealed that high DCLK1 expression was associated with poor prognosis and showed a trend towards higher active NOTCH1 expression in tumors with elevated DCLK1. Our results demonstrate the novel role of DCLK1 as a regulator of NOTCH signaling network and suggest its potential as a therapeutic target in HNSCC.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, with approximately 890,000 new cases and 450,000 deaths associated with the disease [1]
In order to assess the impact that Doublecortin-like kinase 1 (DCLK1) has on head and neck squamous cell carcinoma (HNSCC) tumorigenesis, seven head and neck cell lines including, JHU029, JHU-022, SCC25, JHU011, FaDu, Cal27 and SCC22b, were treated with a small molecule kinase inhibitor LRRK2-IN-1, which was reported to potently inhibit DCLK1 kinase activity [31, 32]
In order to confirm that the phenotype observed in HNSCC cell lines treated with LRRK2IN-1 resulted from a direct inhibition of DCLK1 activity, we utilized a DCLK1 specific small interfering RNA to reduce its expression in selected HNSCC cell lines (JHU-011, JHU-022, JHU-029 and SCC22b) with high endogenous DCLK1 expression
Summary
Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide, with approximately 890,000 new cases and 450,000 deaths associated with the disease [1]. Despite recent advances in diagnosis and treatment approaches, the survival rates for HNSCC have remained largely unchanged, with a 50% 5-year survival [5]. Large-scale genomic and gene expression studies have provided insight into the mutational patterns and molecular pathways in the development of these tumors [6,7,8], few targets have translated into effective molecularly targeted therapies in the clinic. The identification of actionable drug targets for HNSCC has been hindered by the low frequency of targetable oncogene aberrations and the predominance of lossof-function mutations in tumor suppressor genes, which are difficult to drug and correct directly [8]. There is an urgent need to identify molecular drivers of HNSCC carcinogenesis that can be targeted therapeutically
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