Emerging Roles of DLK1 in the Stem Cell Niche and Cancer Stemness

Grassi, Elisa; Pietras, Alexander

doi:10.1369/00221554211048951

Cited by 21 publications

(17 citation statements)

References 102 publications

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“…Jag1, a canonical Notch ligand, functioned as an activator of Notch receptors on adjacent cells. Dlk1, a non‐canonical Notch ligand, is a member of the epidermal growth factor‐like repeat‐containing family of proteins [ 36 ]. Increasing evidence indicates that Dlk1 functions as a secreted or transmembrane protein, and interacted with Notch to act as a negative regulator of Notch activation and signaling [ 37 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

Reversine attenuates cholestatic ductular reaction in rats

Huang

Tang

et al. 2023

FEBS Open Bio

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Ductular reaction (DR) is usually observed in biliary disorders or various liver disorders, including nonalcoholic fatty liver disease. Few studies have focused on interrupting the DR process in the cholestatic environment. Here, we investigated the impact of reversine on DR in rats that had undergone bile duct ligation (BDL). Cholestatic injury was induced in rats 2 weeks following BDL. DR was assessed with biliary markers by immunohistochemistry. Biliary epithelial cells (BECs) were isolated for the analysis of proliferation and biliary factor gene expression. The effects of reversine on DR and fibrosis were analyzed in vivo via intraperitoneal injection in rats for 2 weeks. Chemically‐induced BEC formation was used to investigate the biliary markers affected by reversine in vitro . DR with increased BEC expansion was identified in cholestatic liver injury, as indicated by CK7, CK19, and EpCAM expression around the portal vein in BDL rats. BDL‐induced DR cells showed the increased expression of genes regulating cell proliferation ( Ki67 , Foxm1 , and Pcna ) and biliary markers ( Krt7 , Krt19 , Epcam , Sox9 , Cftr , and Asbt ). Reversine attenuated cholestatic fibrosis and DR in rats. Reversine affected chemically‐induced BEC formation, with the decreased expression of biliary Krt7 , Cftr , and Ggt1 genes in vitro . BDL‐induced Notch activation was attenuated upon reversine treatment in vivo , in part via the Notch/Sox9 pathway. In conclusion, reversine attenuated cholestatic ductular reaction and fibrosis in rats and reduced the bile duct formation associated with Dlk1/Notch/Sox9 signaling. Reversine may be regarded as a potential drug for cholangiopathies for preventing a ductular reaction.

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Section: Discussionmentioning

confidence: 99%

Reversine attenuates cholestatic ductular reaction in rats

Huang

Tang

et al. 2023

FEBS Open Bio

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“…Membrane-bound DLK1 is a dominant form that promotes angiogenesis. DLK1 is synthesized as a membrane-bound precursor that has a signal peptide, six EGF-like extracellular repeats, a juxta-membrane region and a short intracellular tail 30 . DLK1 can function as either a membrane-bound or soluble protein, and these two forms likely have different biological functions 27 .…”

Section: Discussionmentioning

confidence: 99%

Delta-like factor 1 negatively regulates angiogenesis as a target gene of miR-126-5p after indirect revascularization surgery in patients with moyamoya disease

et al. 2022

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Promoting endothelial cell (EC) proliferation and angiogenesis after indirect revascularization surgery is crucial for decreasing the stroke rate in moyamoya patients. However, the role of delta-like factor 1 (DLK1) in regulating EC proliferation in chronically ischaemic brains and the specific mechanisms remain unclear. Therefore, we compared the expression levels of DLK1 in the dura mater (DM) tissues of patients with moyamoya disease and patients with aneurysms, and dual luciferase reporter and RNA binding protein immunoprecipitation assays were conducted to determine whether DLK1 is a target gene of miR-126-5p. The effect of DLK1 on EC proliferation and the interaction between DLK1 and miR-126-5p were explored in vitro. Then, we established an animal model of two-vessel occlusion together with encephalo-myo-synangiosis (2VO+EMS). The temporalis muscles (TMs) of the animals were transfected with DLK1 lentiviral RNA (Lv-DLK1) and short hairpin RNA (sh-DLK1) to compare the DLK1 expression, angiogenesis (CD31 count), and numbers of vacuoles and impaired tight junctions in the ECs of TM-covered chronically ischaemic brains as well as the cognitive improvement in each group. DLK1 expression was lower in the DM tissues of moyamoya patients than in those of the aneurysm patients, and DLK1 was identified as a target gene of miR-126-5p. In vitro, DLK1 inhibited EC proliferation, migration and angiogenesis and exerted effects opposite those of miR-126-5p. In 2VO+EMS rats, compared to the control transfection, the TM transfection of Lv-DLK1 induced significantly higher DLK1 expression and worse angiogenesis in the TM-covered ischaemic brain as well as less extensive cognitive improvement, while the transfection of sh-DLK1 into the TM had the opposite effects. In summary, DLK1, a target gene of miR-126-5p, negatively regulates angiogenesis in chronically ischaemic brains and is expected to be a new target to improve the efficacy of indirect revascularization surgery and the prognosis of moyamoya patients.

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“…The α2δ1+ liver CSCs exhibited enhanced self-renewal and tumorigenicity abilities through ERK1/2 phosphorylation compared to the α2δ1- subset [ 54 , 55 ]. Another cell surface protein delta-like 1 protein (DLK1), endowed HCC cells with stronger ability of self-renewal, chemoresistance and tumorigenicity compared to DLK1− cells [ 56 , 57 , 58 ].…”

Section: Intrinsic Molecules and Involved Signaling Pathwaysmentioning

confidence: 99%

Cancer Stem Cells in Hepatocellular Carcinoma: Intrinsic and Extrinsic Molecular Mechanisms in Stemness Regulation

Fang

Yan

Liu

et al. 2022

IJMS

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Hepatocellular carcinoma (HCC) remains the most predominant type of liver cancer with an extremely poor prognosis due to its late diagnosis and high recurrence rate. One of the culprits for HCC recurrence and metastasis is the existence of cancer stem cells (CSCs), which are a small subset of cancer cells possessing robust stem cell properties within tumors. CSCs play crucial roles in tumor heterogeneity constitution, tumorigenesis, tumor relapse, metastasis, and resistance to anti-cancer therapies. Elucidation of how these CSCs maintain their stemness features is essential for the development of CSCs-based therapy. In this review, we summarize the present knowledge of intrinsic molecules and signaling pathways involved in hepatic CSCs, especially the CSC surface markers and associated signaling in regulating the stemness characteristics and the heterogeneous subpopulations within the CSC pool. In addition, we recapitulate the effects of crucial extrinsic cellular components in the tumor microenvironment, including stromal cells and immune cells, on the modulation of hepatic CSCs. Finally, we synopsize the currently valuable CSCs-targeted therapy strategies based on intervention in these intrinsic and extrinsic molecular mechanisms, in the hope of shedding light on better clinical management of HCC patients.

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Emerging Roles of DLK1 in the Stem Cell Niche and Cancer Stemness

Cited by 21 publications

References 102 publications

Reversine attenuates cholestatic ductular reaction in rats

Reversine attenuates cholestatic ductular reaction in rats

Delta-like factor 1 negatively regulates angiogenesis as a target gene of miR-126-5p after indirect revascularization surgery in patients with moyamoya disease

Cancer Stem Cells in Hepatocellular Carcinoma: Intrinsic and Extrinsic Molecular Mechanisms in Stemness Regulation

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