<i>Retracted:</i> DCLK1 promotes epithelial‐mesenchymal transition via the PI3K/Akt/NF‐κB pathway in colorectal cancer

Liu, Weiying; Wang, Shixing; Sun, Qi; Yang, Zhen; Liu, Min; Tang, Hua

doi:10.1002/ijc.31232

Cited by 80 publications

(73 citation statements)

References 41 publications

(91 reference statements)

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“…Currently, accumulating evidence suggests that long-lived DCLK1þ tuft cells may be responsible for colorectal cancer development by participating as tumor-initiating populations with persistent Wnt activation (8). DCLK1 was determined to be responsible for cancer progression via the enhancement of survival (44), self-renewal (44), and epithelial-mesenchymal transition (45,46). Moreover, clinical studies in patients with colorectal cancer demonstrated that DCLK1 was expressed in low-grade adenomas, and its levels increased with worsening severity of dysplasia (47).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness

Park

Kim

Choi

et al. 2019

Clinical Cancer Research

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Purpose: Niclosamide, an FDA-approved anthelmintic drug, has been characterized as a potent Wnt inhibitor that can suppress tumor growth and cancer stem-like cell (CSC) populations. However, the underlying molecular mechanisms remain poorly understood. This study aimed to examine how Wnt inhibition by niclosamide preferentially targets CSCs.Experimental Design: The mechanistic role of niclosamide in CSC inhibition was examined in public databases, human colorectal cancer cells, colorectal cancer xenografts, and azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colorectal cancer model.Results: Niclosamide suppresses CSC populations and their self-renewal activities in colorectal cancer cells, and this CSCtargeting effect leads to irreversible disruption of tumorinitiating potential in vivo. Mechanistically, niclosamide downregulates multiple signaling components of the Wnt pathway, specifically lymphoid enhancer-binding factor 1 (LEF1) expression, which is critical for regulating stemness. Subsequently, we identified that the doublecortin-like kinase 1 (DCLK1)-B is a target of LEF1 and upregulates cancer stemness in colorectal cancer cells. We first documented that niclosamide blocks the transcription of DCLK1-B by interrupting the binding of LEF1 to DCLK1-B promoter. DCLK1-B depletion impairs cancer stemness resulting in reduced survival potential and increased apoptosis, thus sensitizing colorectal cancer to chemoradiation.Conclusions: Disruption of the LEF1/DCLK1-B axis by niclosamide eradicates cancer stemness and elicits therapeutic effects on colorectal cancer initiation, progression, and resistance. These findings provide a preclinical rationale to broaden the clinical evaluation of niclosamide for the treatment of colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness

Park

Kim

Choi

et al. 2019

Clinical Cancer Research

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“…In addition, previous studies have demonstrated that the activation of Akt can significantly trigger NF-κB activation, which promotes the expression of downstream proinflammatory cytokines and gelatinase, and then induces a series of aggressive phenotypes. 38,39 In human glioblastoma cells, the NK-1R agonist can markedly increase the phosphorylation and activity of Akt whereas treatment with the NK-1R antagonist leads to reducing the basal Akt kinase activity, which is involved in the apoptosis. 6,40 Therefore, we focused our attention on the phosphorylation of Akt, which may be a key factor in the SP/NK-1R system.…”

Section: Discussionmentioning

confidence: 99%

SP/NK‐1R promotes gallbladder cancer cell proliferation and migration

Deng

Tang

et al. 2019

J Cellular Molecular Medi

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Aberrant substance P/neurokinin‐1 receptor (SP/NK‐1R) system activation plays a critical role in various disorders, however, little is known about the expression and the detailed molecular mechanism of the SP and NK‐1R in gallbladder cancer (GBC). In this study, we firstly analyzed the expression and clinical significance of them in patients with GBC. Then, cellular assays were performed to clarify their biological role in GBC cells. Moreover, we investigated the molecular mechanisms regulated by SP/NK‐1R. Meanwhile, mice xenografted with human GBC cells were analyzed regarding the effects of SP/NK1R complex in vivo. Finally, patient samples were utilized to investigate the effect of SP/NK‐1R. The results showed that SP and NK‐1R were highly expressed in GBC. We found that SP strongly induced GBC cell proliferation, clone formation, migration and invasion, whereas antagonizing NK‐1R resulted in the opposite effects. Moreover, SP significantly enhanced the expression of NF‐κB p65 and the tumor‐associated cytokines, while, Akt inhibitor could reverse these effects. Further studies indicated that decreasing activation of NF‐κB or Akt diminished GBC cell proliferation and migration. In consistent with results, immunohistochemical staining showed high levels of Akt, NF‐κB and cytokines in tumor tissues. Most importantly, the similar conclusion was obtained in xenograft mouse model. Our findings demonstrate that NK‐1R, after binding with the endogenous agonist SP, could induce GBC cell migration and spreading via modulation of Akt/NF‐κB pathway.

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“…Prevenient researches reported that SP1 participates in the biological function of NF-κB signaling pathways and EMT (27). Transfected SW480 and HCT116 cells were subjected to immunoblotting for SP1, IκBα, phosphorylated IκBα, p65, phosphorylated p65, and EMT proteins (ZO1, E-cadherin, vimentin, and N-cadherin).…”

Section: Nf-κb Signaling Is Essential For the Biological Function Of mentioning

confidence: 99%

MicroRNA-1224-5p Inhibits Metastasis and Epithelial-Mesenchymal Transition in Colorectal Cancer by Targeting SP1-Mediated NF-κB Signaling Pathways

Peng

Yang

et al. 2020

Front. Oncol.

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MicroRNAs (miRNAs) are small non-coding RNAs that play pivotal roles in cancer initiation and progression. However, the roles and molecular mechanisms of miRNAs in colorectal cancer (CRC) progression remain unclear. Here, we show that downregulation of miR-1224-5p in CRC is negatively correlated with SP1 expression and metastasis in patients and xenografted mouse models. Gain-and loss-of-function assays reveal that miR-1224-5p suppresses the migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells in vitro and in vivo by directly targeting SP1. Moreover, SP1 promotes the phosphorylation of p65, which results in EMT progress in CRC cells. Clinical analysis reveals that miR-1224-5p and SP1 expression are remarkably associated with advanced clinical features and unfavorable prognosis of patients with CRC. Further study confirms that hypoxia accounts for the depletion of miR-1224-5p in CRC. The enhancement of hypoxia during epithelial-mesenchymal transition and metastasis of CRC cells is abolished by miR-1224-5p. Our findings provide the first evidence that miR-1224-5p is a potential therapeutic target and prognostic biomarker for patients with CRC.

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Retracted: DCLK1 promotes epithelial‐mesenchymal transition via the PI3K/Akt/NF‐κB pathway in colorectal cancer

Cited by 80 publications

References 41 publications

Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness

Inhibition of LEF1-Mediated DCLK1 by Niclosamide Attenuates Colorectal Cancer Stemness

SP/NK‐1R promotes gallbladder cancer cell proliferation and migration

MicroRNA-1224-5p Inhibits Metastasis and Epithelial-Mesenchymal Transition in Colorectal Cancer by Targeting SP1-Mediated NF-κB Signaling Pathways

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