DCLK1 plays an important role in colorectal cancer tumorgenesis through the regulation of miR-200c

Mohammadi, Yasaman; Tavangar, Seyed Mohammad; Saidijam, Massoud; Amini, Razieh; Etemadi, Katayoon; Dermani, Fatemeh Karimi; Najafi, Rezvan

doi:10.1016/j.biopha.2018.04.042

Cited by 24 publications

(16 citation statements)

References 42 publications

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“…Our results demonstrate that silencing of DCLK1, through either pharmacologic inhibitor or siRNA, significantly inhibited key neoplastic characteristics of the head and neck cancer cell lines, such as proliferation, migration, and invasion, whereas overexpression of DCLK1 in normal keratinocytes induced cell proliferation and survival, and was associated with elevated expression of stemness markers. Although this aligns with prior research in other solid tumors; for instance, increased DCLK1 has been reported to induce pancreatic, colorectal and ovarian cancer cell migration and invasion (51)(52)(53), the mechanisms through which DCLK1 exerts these effects in HNSCC remain largely unknown (17).…”

Section: Discussionsupporting

confidence: 86%

Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma

Broner

Trujillo

Korzinkin³

et al. 2021

Front. Oncol.

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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.

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Section: Discussionsupporting

confidence: 86%

Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma

Broner

Trujillo

Korzinkin³

et al. 2021

Front. Oncol.

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“…In our previous works, oncopathological value of DCLK1 expression was evaluated in various cancers including colorectal, bladder, and gastric carcinomas; results of which were in line with other studies 17,19,23,[27][28][29][30] . In a comprehensive study on 472 bladder cancer cases, an increase was found in expression of DCLK1 (DCLK1-L/S) that associated with more aggressive tumors, advanced stages, and poorer DSS in the patients with bladder cancer 19 .…”

Section: Discussionsupporting

confidence: 83%

Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

Kalantari

Ghods

Zanjani

et al. 2021

Preprint

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Isoform-specific function of doublecortin-like kinase 1(DCLK1) has highlighted key role of the DCLK1-S (short isoform) in maintenance, progression, and invasion of tumor. Therefore, this study was designed to produce an anti-DCLK1-S polyclonal antibody in order to specifically evaluate expression pattern and clinical significance of DCLK1-S in a well-deﬁned tissue microarray (TMA) series of colorectal tissues including 348 colorectal cancer (CRC) and 51 adjacent normal tissues during a follow-up period of 108 months. Expression of DCLK1-S was significantly higher in CRC samples compared to adjacent normal samples (P < 0.001). Cytoplasmic expression of DCLK1-S was significantly higher in the tumors at advanced stage of the cancer and with poorer differentiation (P<0.001, P= 0.02). The patients with CRC whose tumors showed higher cytoplasmic expression of DCLK1-S had worse disease-specific survival (DSS) (log-rank test, P = 0.03) and 5-year DSS rates (P= 0.01). Additionally, an improved prognostic value was observed in the patients with CRC with high DCLK1-S expression vs. its moderate expression (HR: 2.70, 95% CI: 0.98-7.38; p =0.04) by multivariate analysis. Our findings strongly supported that high cytoplasmic expression of DCLK1-S compared to its moderate expression could be considered as an independent prognostic factor influencing DSS. Taken together, DCLK1-S can be a promising prognostic candidate and targeted-therapeutic indicator for effective treatment of CRC.

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“…In our previous works, oncopathological value of DCLK1 expression was evaluated in various cancers including colorectal, bladder, and gastric carcinomas; results of which were in line with other studies [17,19,36,[40][41][42][43]. In a comprehensive study on 472 bladder cancer cases, an increase was found in expression of DCLK1 (DCLK1-L/S) that associated with more aggressive tumors, advanced stages, and poorer DSS in the patients with bladder cancer [19].…”

Section: Discussionsupporting

confidence: 78%

Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

Kalantari

Ghods

Zanjani

et al. 2021

Preprint

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Background: Oncogenic role of doublecortin-like kinase 1 (DCLK1) as a putative cancer stem cell (CSC) marker has been clarified in colorectal cancer (CRC). Isoform-specific function of DCLK1 has highlighted key role of the DCLK1-S (short isoform) in tumor maintenance, progression, and invasion. Considering the lack of commercial anti-DCLK1-S antibody suitable for immunohistochemical (IHC) application, this study was conducted to produce and validate an anti-DCLK1-S polyclonal antibody in order to specifically evaluate expression pattern and clinical significance of short isoform of DCLK1 in colorectal cancer tissues.Methods: Rabbit immunization was performed against a synthetic peptide corresponding to the published six specific amino acid sequences of DCLK1-S, and production of antibody was evaluated by enzyme-linked immunosorbent assay (ELISA). After IHC assessment of the purified anti-DCLK1-S polyclonal antibody, it was used to undertake a definitive study for determining prognostic significance of DCLK1-S expression in a well-deﬁned tissue microarray (TMA) series including 348 CRC and 51 adjacent normal tissues with a follow-up period of 108 months. Results: Positive immunoreactivity of DCLK1-S was found in 84.2% of CRC samples. Cytoplasmic expression was the main localization of DCLK1-S compared to nuclear and membranous area of tumor cells. Expression of DCLK1-S in CRC samples was significantly higher compared to adjacent normal samples (P <0.001). A positive significant association was found between high cytoplasmic expression of DCLK1-S and advanced tumor, nodes, and metastases (TNM) stage (P<0.001) as well as the increased tumor differentiation (P= 0.02). Moreover, the patients with CRC whose tumors showed higher cytoplasmic expression of DCLK1-S had worse disease-specific survival (DSS) (log-rank test, P = 0.03) and 5-year DSS rate (P= 0.01). Additionally, the improved prognostic value was seen in the patients with CRC with high DCLK1-S expression versus moderate expression (HR: 2.70, 95% CI: 0.98-7.38; p =0.04) by multivariate analysis.Conclusions: Our findings strongly supported that DCLK1-S isoform may play a crucial role in invasion, tumor aggressive behavior, and worsened DSS of the patients with CRC. Importantly, high cytoplasmic expression of DCLK1-S compared to moderate expression could be considered as an independent prognostic factor influencing DSS. Taken together, DCLK1-S can be a candidate as a promising prognostic and targeted-therapeutic indicator for effective treatment of CRC.

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DCLK1 plays an important role in colorectal cancer tumorgenesis through the regulation of miR-200c

Cited by 24 publications

References 42 publications

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

Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

Cytoplasmic Expression of DCLK1-S, a Novel DCLK1 Isoform, Is Associated with Tumor Aggressiveness and Worse Disease-Specific Survival in Colorectal Cancer

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