Increased DCLK1 correlates with the malignant status and poor outcome in malignant tumors: a meta-analysis

Shi, Wenhua; Li, Fangwei; Li, Shaojun; Wang, Jian; Wang, Qingting; Yan, Xin; Zhang, Qianqian; Chai, Limin; Li, Manxiang

doi:10.18632/oncotarget.20129

Cited by 12 publications

(15 citation statements)

References 36 publications

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“…Since the detection as a marker in cancer stem cells, DCLK1 has attracted attention of researchers from the field of oncology. Accumulating evidence indicates that DCLK1 expression is associated with advanced cancer stages and poor clinical prognosis [32] . Hence, whether or not DCLK1 directly drives cancers, DCLK1 is regarded as a critical biomarker in cancers.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability

Maruyama

Kuwata³

et al. 2018

Biochemistry and Biophysics Reports

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Doublecortin-like kinase 1 (DCLK1) is a serine/threonine-kinase with two doublecortin (DCX) domains. DCLK1 is associated with microtubules via DCX domains and regulates microtubule polymerization. DCLK1 is known to be expressed in cancer stem cells and provides cancer cells with tumor-initiating capacity. Accumulating clinical evidence supports that DCLK1 is associated with tumor aggressiveness and is an important prognostic marker in various human cancers. However, the mechanism, by which DCLK1 causes oncogenesis, is not yet elucidated. In this study, we showed that DCLK1 empowers human mammary epithelial MCF10A cells to form spheres under floating condition in serum-free medium, which are reminiscent of mammospheres formed by mammary epithelial stem cells. We demonstrated that DCLK1 causes chromatin instability in MCF10A cells. DCLK1 impairs DNA repairs in human colon cancer HCT116 and lung cancer H1299 cells. The kinase-negative DCLK1 mutant and the mutant that is not associated with microtubules compromise DNA repair. In conclusion, DCLK1 interferes with DNA repair and induces tumorigenesis through genomic instability and this function is independent of the kinase activity and the regulation of microtubules.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability

Maruyama

Kuwata³

et al. 2018

Biochemistry and Biophysics Reports

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“…Intriguingly, p62 seems to co-localize with Dclk1 as a punctate staining at the plasma membrane while occasional co-localization could be seen within the nucleus. Since Dclk1 exists in a membrane-bound long (Dclk1-L) and membrane/nuclear localized short (Dclk1-S) forms consistent with presence of both transcripts coded for by α- and β-promoters respectively [24], our findings suggest that both isoforms of Dclk1 are probably involved in the tumorigenic process. The increases in Dclk1-L and Dclk1-S promoter activities following treatment with either autophagy inhibitor CQ or LPS further support our conclusion.…”

Section: Discussionmentioning

confidence: 57%

“…Prior studies have shown that a subset of Dclk1-positive CSCs survive due to autophagy in response to curcumin [23] and that increased Dclk1 correlates with the malignant status and poor outcome in malignant tumors [24]. We next examined surgical samples from a patient with multiple tumors in the colon and metastasis to the liver.…”

Section: Resultsmentioning

confidence: 99%

“…In line with this observation, our findings provide a more comprehensive look into the complexity of Dclk1 regulation during tumorigenesis and suggest that Dclk1+ cells may survive due to impaired autophagy. Since it is generally believed that autophagy contributes to stemness maintenance of CSCs [15] and increases in Dclk1 correlates with the malignant status and poor outcome in malignant tumors [24], our studies provide a rationale to capture these interactions early through small molecule inhibitor-based Dclk1 targeting to block Dclk1 from interacting with p62 as a strategy to prevent or treat colon cancer.…”

Section: Discussionmentioning

confidence: 99%

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Co-localization of autophagy-related protein p62 with cancer stem cell marker dclk1 may hamper dclk1's elimination during colon cancer development and progression

et al. 2019

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Autophagy may play a critical role in colon cancer stem cells (CCSCs)-related cancer development. Here, we investigate whether accumulation of infection/injury-induced CCSCs due to impaired autophagy influences colon cancer development and progression. When Apc ++ mice were infected with Citrobacter rodentium (CR; 10 9 CFUs), we discovered presence of autophagosomes with increases in Beclin-1, LC3B and p62 staining during crypt hyperplasia. Apc1638N/+ mice when infected with CR or subjected to CR+AOM treatment, exhibited increased colon tumorigenesis with elevated levels of Ki-67, β-catenin, EZH2 and CCSC marker Dclk1, respectively. AOM/DSS treatment of Apc1638N/+ mice phenocopied CR+AOM treatment as colonic tumors exhibited pronounced changes in Ki-67, EZH2 and Dclk1 accompanied by infiltration of F4/80+ macrophages, CD3+ lymphocytes and CD3/β-catenin co-localization. Intestinal and colonic tumors also stained positive for migrating CSC markers CD110 and CDCP1 wherein, colonic tumors additionally exhibited stromal positivity. In tumors from CR-infected, CR+AOM or AOM/DSS-treated Apc1638N/+ mice and surgically-resected colon tumor/metastatic liver samples, significant accumulation of p62 and it's co-localization with LC3B and Dclk1 was evident. Apc Min/+ mice when infected with CR and BLT1 −/− ;Apc Min/+ mice, exhibited similar co-localization of p62 with LC3B and Dclk1 within the tumors. Studies in HCT116 and SW480 cells further confirmed p62/Dclk1 co-localization and Chloroquin/LPS-induced increases in Dclk1 promoter activity. Thus, co-localization of p62 with Dclk1 may hamper Dclk1's elimination to impact colon cancer development and progression.

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“…Although Dclk1 was first described as a brain-specific gene, the roles of Dclk1 outside the nervous system have recently been the main area of study. Dclk1 is expressed in a variety of cancer cells [ 23 ], with a functional role in tumor growth and progression. However, its general role in carcinogenesis and clinical significance as a potential diagnostic marker remain unclear [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of alternatively spliced variants of the Dclk1 gene is regulated by psychotropic drugs

et al. 2018

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BackgroundThe long-term effects of psychotropic drugs are associated with the reversal of disease-related alterations through the reorganization and normalization of neuronal connections. Molecular factors that trigger drug-induced brain plasticity remain only partly understood. Doublecortin-like kinase 1 (Dclk1) possesses microtubule-polymerizing activity during synaptic plasticity and neurogenesis. However, the Dclk1 gene shows a complex profile of transcriptional regulation, with two alternative promoters and exon splicing patterns that suggest the expression of multiple isoforms with different kinase activities.ResultsHere, we applied next-generation sequencing to analyze changes in the expression of Dclk1 gene isoforms in the brain in response to several psychoactive drugs with diverse pharmacological mechanisms of action. We used bioinformatics tools to define the range and levels of Dclk1 transcriptional regulation in the mouse nucleus accumbens and prefrontal cortex. We also sought to investigate the presence of DCLK1-derived peptides using mass spectrometry. We detected 15 transcripts expressed from the Dclk1 locus (FPKM > 1), including 2 drug-regulated variants (fold change > 2). Drugs that act on serotonin receptors (5-HT2A/C) regulate a subset of Dclk1 isoforms in a brain-region-specific manner. The strongest influence was observed for the mianserin-induced expression of an isoform with intron retention. The drug-activated expression of novel alternative Dclk1 isoforms was validated using qPCR. The drug-regulated isoform contains genetic variants of DCLK1 that have been previously associated with schizophrenia and hyperactivity disorder in humans. We identified a short peptide that might originate from the novel DCLK1 protein product. Moreover, protein domains encoded by the regulated variant indicate their potential involvement in the negative regulation of the canonical DCLK1 protein.ConclusionsIn summary, we identified novel isoforms of the neuroplasticity-related gene Dclk1 that are expressed in the brain in response to psychotropic drug treatments.Electronic supplementary materialThe online version of this article (10.1186/s12868-018-0458-4) contains supplementary material, which is available to authorized users.

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Increased DCLK1 correlates with the malignant status and poor outcome in malignant tumors: a meta-analysis

Cited by 12 publications

References 36 publications

RETRACTED: Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability

RETRACTED: Doublecortin-like kinase 1 compromises DNA repair and induces chromosomal instability

Co-localization of autophagy-related protein p62 with cancer stem cell marker dclk1 may hamper dclk1's elimination during colon cancer development and progression

Expression of alternatively spliced variants of the Dclk1 gene is regulated by psychotropic drugs

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