DCLK1 promotes colorectal cancer stemness and aggressiveness via the XRCC5/COX2 axis

Kim, Jee-Heun; Park, So‐Yeon; Jeon, So-El; Choi, Jang-Hyun; Lee, Choong-Jae; Jang, T.; Yun, Hyeon-Ji; Lee, Yuno; Kim, Pilho; Cho, Sang‐Hee; Lee, Ji Shin; Nam, Jeong‐Seok

doi:10.7150/thno.72037

Cited by 22 publications

(20 citation statements)

References 83 publications

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“…been described in their regulation of prostaglandins, while little to no research is available on the other LM classes [42][43][44][45]. Mef2a and Mef2c have been identified as downstream effectors of PGE2, which could indicate a feedback loop on prostaglandin e synthesis [46,47].…”

Section: Cell-type-specific Gene Regulationmentioning

confidence: 99%

Cell-Type-Specific Gene Regulatory Networks of Pro-Inflammatory and Pro-Resolving Lipid Mediator Biosynthesis in the Immune System

Rauthe

Cesnulevicius

Schultz

et al. 2023

IJMS

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Lipid mediators are important regulators in inflammatory responses, and their biosynthetic pathways are targeted by commonly used anti-inflammatory drugs. Switching from pro-inflammatory lipid mediators (PIMs) to specialized pro-resolving (SPMs) is a critical step toward acute inflammation resolution and preventing chronic inflammation. Although the biosynthetic pathways and enzymes for PIMs and SPMs have now been largely identified, the actual transcriptional profiles underlying the immune cell type-specific transcriptional profiles of these mediators are still unknown. Using the Atlas of Inflammation Resolution, we created a large network of gene regulatory interactions linked to the biosynthesis of SPMs and PIMs. By mapping single-cell sequencing data, we identified cell type-specific gene regulatory networks of the lipid mediator biosynthesis. Using machine learning approaches combined with network features, we identified cell clusters of similar transcriptional regulation and demonstrated how specific immune cell activation affects PIM and SPM profiles. We found substantial differences in regulatory networks in related cells, accounting for network-based preprocessing in functional single-cell analyses. Our results not only provide further insight into the gene regulation of lipid mediators in the immune response but also shed light on the contribution of selected cell types in their biosynthesis.

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Section: Cell-type-specific Gene Regulationmentioning

confidence: 99%

Cell-Type-Specific Gene Regulatory Networks of Pro-Inflammatory and Pro-Resolving Lipid Mediator Biosynthesis in the Immune System

Rauthe

Cesnulevicius

Schultz

et al. 2023

IJMS

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“…DCLK1 is an enzyme that regulates epithelial mesenchymal transition ( 43 ). Mesenchymal DCLK1 labeling of tumor stem cells in a genetic mouse model of CRC ( 44 ). DCLK1-targeted CAR-T cells therapy inhibited xenograft tumor growth in mice without apparent toxicity ( 45 ).…”

Section: Basic Experimental Of Car-t Cells Therapy For Crcmentioning

confidence: 99%

Recent advances in CAR-T cells therapy for colorectal cancer

Qin

Chen

et al. 2022

Front. Immunol.

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Colorectal cancer (CRC) is the third most common cancer, with a high mortality rate and a serious impact on people’s life and health. In recent years, adoptive chimeric antigen receptor T (CAR-T) cells therapy has shown well efficacy in the treatment of hematological malignancies, but there are still many problems and challenges in solid tumors such as CRC. For example, the tumor immunosuppressive microenvironment, the low targeting of CAR-T cells, the short time of CAR-T cells in vivo, and the limited proliferation capacity of CAR-T cells, CAR-T cells can not effectively infiltrate into the tumor and so on. New approaches have been proposed to address these challenges in CRC, and this review provides a comprehensive overview of the current state of CAR-T cells therapy in CRC.

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“…Recently, DCLK1 has been reported to play an important role in inflammatory diseases. Kim et al ( 2022 ) reported that DCLK1 promotes colorectal cancer by generating an inflammatory tumor microenvironment. Roy et al ( 2021 ) determined that the Notch‐DCLK1 axis is integral to colitis progression.…”

Section: Introductionmentioning

confidence: 99%

“…Since then, a number of studies have shown a range of DCLK1 activities in tumorigenesis (Sureban et al, 2014;Chandrakesan et al, 2017). Increased levels of DCLK1 have also been reported in various human cancers (Nevi et al, 2021;Kim et al, 2022). Recently, DCLK1 has been reported to play an important role in inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses

et al. 2023

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Atherosclerosis is a chronic inflammatory disease with high morbidity and mortality rates worldwide. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein kinase, is involved in neurogenesis and human cancers. However, the role of DCLK1 in atherosclerosis remains undefined. In this study, we identified upregulated DCLK1 in macrophages in atherosclerotic lesions of ApoE −/− mice fed an HFD and determined that macrophagespecific DCLK1 deletion attenuates atherosclerosis by reducing inflammation in mice. Mechanistically, RNA sequencing analysis indicated that DCLK1 mediates oxLDL-induced inflammation via NF-κB signaling pathway in primary macrophages. Coimmunoprecipitation followed by LC-MS/MS analysis identified IKKβ as a binding protein of DCLK1. We confirmed that DCLK1 directly interacts with IKKβ and phosphorylates IKKβ at S177/181, thereby facilitating subsequent NF-κB activation and inflammatory gene expression in macrophages. Finally, a pharmacological inhibitor of DCLK1 prevents atherosclerotic progression and inflammation both in vitro and in vivo. Our findings demonstrated that macrophage DCLK1 promotes inflammatory atherosclerosis by binding to IKKβ and activating IKKβ/NF-κB. This study reports DCLK1 as a new IKKβ regulator in inflammation and a potential therapeutic target for inflammatory atherosclerosis.

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DCLK1 promotes colorectal cancer stemness and aggressiveness via the XRCC5/COX2 axis

Cited by 22 publications

References 83 publications

Cell-Type-Specific Gene Regulatory Networks of Pro-Inflammatory and Pro-Resolving Lipid Mediator Biosynthesis in the Immune System

Cell-Type-Specific Gene Regulatory Networks of Pro-Inflammatory and Pro-Resolving Lipid Mediator Biosynthesis in the Immune System

Recent advances in CAR-T cells therapy for colorectal cancer

Macrophage DCLK1 promotes atherosclerosis via binding to IKKβ and inducing inflammatory responses

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