Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma.
Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma.
复制标题
双皮质素样激酶1（DCLK1）是头颈部鳞状细胞癌中一种新的NOTCH通路信号调节因子。
DOI：
10.3389/fonc.2021.677051
复制
发表时间：
2021
影响因子：
4.7
通讯作者：
Izumchenko E
中科院分区：
文献类型：
--
作者：
Broner EC;Trujillo JA;Korzinkin M;Subbannayya T;Agrawal N;Ozerov IV;Zhavoronkov A;Rooper L;Kotlov N;Shen L;Pearson AT;Rosenberg AJ;Savage PA;Mishra V;Chatterjee A;Sidransky D;Izumchenko E
尽管最近的进展，头颈部鳞状细胞癌（HNSCC）的5年生存率徘徊在60%。DCLK1已被证明可以调节上皮细胞向间充质细胞的转化，并在结肠癌、胰腺癌和肾癌中充当癌症干细胞标志物。尽管有报道称DCLK1与口咽癌的不良预后相关，但对HNSCC中DCLK1的分子特征知之甚少。在这项研究中，我们对来自TCGA和GEO数据库的数百名HNSCC患者进行了全面的基于转录组的计算分析，发现DCLK1表达与NOTCH信号通路激活呈正相关。由于NOTCH信号传导在HNSCC肿瘤发生中具有公认的作用，我们接下来在一系列HNSCC细胞系中进行了一系列体外实验，以研究DCLK1在NOTCH途径调节中的作用。我们的分析显示，使用药理学抑制剂或siRNA抑制DCLK1，导致增殖、侵袭、迁移和集落形成显著降低。此外，这些作用包括活性NOTCH 1及其下游效应物HEY 1、HES 1和HES 5的下调，而正常角质形成细胞中DCLK 1的过表达导致与增殖增加相关的NOTCH信号传导的上调。对233例原发性和40例复发性HNSCC癌活检的分析显示，DCLK1高表达与预后不良相关，并且在DCLK1升高的肿瘤中显示出更高活性NOTCH 1表达的趋势。我们的研究结果表明DCLK1作为NOTCH信号网络的调节剂的新作用，并表明其作为HNSCC治疗靶点的潜力。
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.
登录
查看更多内容
影响因子：
2.6
作者：
Kadletz, Lorenz;Aumayr, Klaus;Lill, Claudia
通讯作者：
Lill, Claudia
影响因子：
4.6
作者：
Kunze B;Middelhoff M;Maurer HC;Agibalova T;Anand A;Bührer AM;Fang HY;Baumeister T;Steiger K;Strangmann J;Schmid RM;Wang TC;Quante M
通讯作者：
Quante M
DOI：
10.1158/1940-6207.capr-14-0257
发表时间：
2015-04
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Izumchenko E;Sun K;Jones S;Brait M;Agrawal N;Koch W;McCord CL;Riley DR;Angiuoli SV;Velculescu VE;Jiang WW;Sidransky D
通讯作者：
Sidransky D
影响因子：
4.2
作者：
Gavai, Ashvinikumar V.;Quesnelle, Claude;Lee, Francis Y.
通讯作者：
Lee, Francis Y.
影响因子：
4.6
作者：
Aladegbami B;Barron L;Bao J;Colasanti J;Erwin CR;Warner BW;Guo J
通讯作者：
Guo J