Broner Esther C, Trujillo Jonathan A, Korzinkin Michael, Subbannayya Tejaswini, Agrawal Nishant, Ozerov Ivan V, Zhavoronkov Alex, Rooper Lisa, Kotlov Nikita, Shen Le, Pearson Alexander T, Rosenberg Ari J, Savage Peter A, Mishra Vasudha, Chatterjee Aditi, Sidransky David, Izumchenko Evgeny
Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University, School of Medicine, Baltimore, MD, United States.
Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, United States.
Front Oncol. 2021 Jul 16;11:677051. doi: 10.3389/fonc.2021.677051. eCollection 2021.
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 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.
尽管最近取得了进展，但头颈部鳞状细胞癌（HNSCC）的5年生存率仍徘徊在60%。DCLK1已被证明可调节上皮-间质转化，并在结肠癌、胰腺癌和肾癌中作为癌症干细胞标志物。虽然有报道称DCLK1与口咽癌的预后不良有关，但对于HNSCC中DCLK1的分子特征知之甚少。在本研究中，我们对来自TCGA和GEO数据库的数百名HNSCC患者进行了基于转录组的全面计算分析，发现DCLK1表达与NOTCH信号通路激活呈正相关。由于NOTCH信号在HNSCC肿瘤发生中具有公认的作用，我们接下来在一组HNSCC细胞系中进行了一系列实验，以研究DCLK1在NOTCH通路调节中的作用。我们的分析表明，使用药理抑制剂或siRNA抑制DCLK1会导致增殖、侵袭、迁移和集落形成显著减少。此外，这些效应与活性NOTCH1及其下游效应分子HEY1、HES1和HES5的下调平行，而在正常角质形成细胞中过表达DCLK1会导致NOTCH信号上调，伴随着增殖增加。对233例原发性和40例复发性HNSCC癌活检组织进行分析发现，DCLK1高表达与预后不良相关，并且在DCLK1升高的肿瘤中显示出活性NOTCH1表达更高的趋势。我们的结果证明了DCLK1作为NOTCH信号网络调节剂的新作用，并表明其作为HNSCC治疗靶点的潜力。
