DCLK1 expression in gastrointestinal stem cells and neoplasia

Bellows, Charles F.; Gagliardi, Giuseppe

doi:10.7243/2049-7962-1-12

Cited by 11 publications

(10 citation statements)

References 49 publications

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“…In this study we started to select miRNAs using doublecortin-like kinase 1 (DCLK1) as a target [18,45] as well as Notch and Wnt signaling ( Supplementary Fig. S1).…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor effect of miR-1291 in colorectal cancer

Wang

Hirose

Yokoyama

et al. 2020

Preprint

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Background: MiR-1291 has an anti-tumor effect in carcinoma of kidney, esophagus, pancreas, and prostate. However, it’s role in colorectal cancer (CRC) has not been elucidated.Methods: In this study, we explored the effect of miR-1291 in CRC cells (HCT116, DLD-1, and HT29) in vitro, and performed a tumor growth inhibitory assay in a mouse therapeutic model using DLD-1 cells. Flow cytometric analysis and Western blotting were performed to examine a role of miR-1291 in cell cycle regulation. We performed luciferase reporter assay to verify the interaction between DCLK1 and miR-1291 in HCT116 cells. Cancer stemness was evaluated by identifying the expression of BMI1 and CD133, as well as performing sphere formation assay. Results: We found that miR-1291 significantly suppressed the proliferation, invasion, cell mobility, and colony formation capability of CRC cell lines. MiR-1291 caused altered expression of the cell cycle-regulatory proteins, representatively CDK inhibitors p21WAF1/CIP1 and p27KIP1 or CDK4. Moreover, intravenous administration of miR-1291 loaded on the super carbonate apatite delivery system significantly inhibited a tumor growth in the DLD-1 xenograft mouse model. A luciferase reporter assay showed that miR-1291 directly bound the 3’ UTR sequence of DCLK1 and suppressed its expression at both the mRNA and protein levels in HCT116 expressing the DCLK1 protein. In addition, miR-1291 suppressed cancer stem cell (CSC) markers BMI1 and CD133 as well as sphere formation ability in HCT116 cells. Conclusions: Taken together, these findings indicate that miR-1291 has an anti-tumor effect by modulating multiple functions, including cell cycle, invasiveness, and cancer stemness. Our data suggest that miR-1291 could be a promising nucleic acid medicine against CRC.

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“…In this study we started to select miRNAs using doublecortin-like kinase 1 (DCLK1) as a target [18,45] as well as Notch and Wnt signaling ( Supplementary Fig. S1).…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor effect of miR-1291 in colorectal cancer

Wang

Hirose

Yokoyama

et al. 2020

Preprint

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“…Thus, they cannot be considered quiescent or active intestinal stem cells ( 30 ). DCLK1 helps in maintaining intestinal homeostasis, along with assisting tissue regeneration ( 8 , 31 – 32 ). Thus, knocking down DCLK1 in mouse models of DDS-induced colitis followed by completely irradiating it results in the loss of DCLK1, exacerbating tissue injury and halting the tissue regeneration ( 33 , 34 ).…”

Section: Functions Of Dclk1 and Its Role In Cancermentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…DCLK1 is expressed in tuft cells of the gastrointestinal tract, and is also expressed at low levels in normal gastrointestinal cells and upregulated in several gastrointestinal malignancies ( 8 ). It is also considered a marker in cancer stem cells and cancer-initiating cells ( 8 – 11 ). The DCLK1 gene is speculated to serve a role in the epithelial-to-mesenchymal transition (EMT) of tumor cells by regulating the NOTCH, WNT and NFKB signaling pathways ( 12 , 13 ).…”

Section: Introductionmentioning

confidence: 99%

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DCLK1 and its interaction partners: An effective therapeutic target for colorectal cancer (Review)

et al. 2021

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Doublecortin-like kinase protein 1 (DCLK1) is a microtubule-associated protein with a C-terminal serine/threonine kinase domain. Its expression was first reported in radial glial cells, where it serves an essential role in early neurogenesis, and since then, other functions of the DCLK1 protein have also been identified. Initially considered to be a marker of quiescent gastrointestinal and pancreatic stem cells, DCLK1 has recently been identified in the gastrointestinal tract as a marker of tuft cells. It has also been implicated in different types of cancer, where it regulates several vital pathways, such as Kras signaling. However, its underlying molecular mechanisms remain unclear. The present review discusses the different roles of DCLK1 and its interactions with other proteins that are homologically similar to DCLK1 to develop a novel therapeutic strategy to target cancer cells more accurately.

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“…Several CSC markers for CRC have been found, including CD133, Bmi1, and Lgr5 [17][18][19]. Recently, doublecortin-like kinase 1 (DCLK-1) was demonstrated to be a CSC marker in CRC [20,21]. DCLK-1 belongs to the protein kinase superfamily and the doublecortin family, and is over-expressed in several human malignancies, including colon, pancreas, kidney, and prostate cancer [22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Anti-tumor effect of miR-1291 in colon cancer cells

Wang

Hirose

Yokoyama

et al. 2020

Preprint

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Background: Cancer stem cells (CSCs) are drug-tolerant and cause distant metastasis and recurrence in various cancers, including colorectal cancer (CRC). Thus, CSC-targeted therapy may be an effective curative approach in CRC. MiR-1291 has an anti-tumor effect in carcinoma of kidney, esophagus, pancreas, and prostate. However, there is no report about the effect of miR-1291 on CRC.Methods: In this study, we took CSC marker DCLK-1 as a target gene, and screened promising miRNAs that may suppress DCLK-1 by using TargetScan Human. We performed luciferase reporter assay, quantitative real-time PCR analysis, and Western blot analysis to verify the interaction between DCLK-1 and miR-1291 in CRC cells. We also confirmed the function of miR-1291 on cancer stemness by identifying the expression of Bmi1 and CD133 in CRC cells by quantitative real-time PCR analysis, Western blot analysis, and flow cytometric analysis, as well as performing sphere formation assay. We also explored the effect of miR-1291 on cell proliferation, invasion, and wound-healing, colony formation, and cell cycle regulation. Results: We found a 7-base seed sequence of miR-1291 that matches the 3’ UTR sequence of DCLK-1 using TargetScan Human. A luciferase reporter assay showed that miR-1291 directly bound the 3’ UTR sequence of DCLK-1 and suppressed its expression at both the mRNA and protein levels. In addition, miR-1291 suppressed CSC markers Bmi1 and CD133 as well as sphere formation ability in CRC cells. Moreover, miR-1291 significantly suppressed the proliferation, invasion, wound-healing, and colony formation capability of colon cancer cell lines. MiR-1291 caused altered expression of the cell cycle-regulatory proteins representatively, CDK inhibitors p21WAF1/CIP1 and p27KIP1. Conclusions: Taken together, these findings indicate that miR-1291 has an anti-tumor effect by modulating multiple functions, including, cancer stemness, cell cycle, and invasiveness. Our data suggest that miR-1291 could be a promising nucleic acid medicine against CRC.

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DCLK1 expression in gastrointestinal stem cells and neoplasia

Cited by 11 publications

References 49 publications

Anti-tumor effect of miR-1291 in colorectal cancer

Anti-tumor effect of miR-1291 in colorectal cancer

DCLK1 and its interaction partners: An effective therapeutic target for colorectal cancer (Review)

Anti-tumor effect of miR-1291 in colon cancer cells

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