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Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer

ABSTRACT: We report that NEK2 protein level is overexpressed and correlated with the tumor stage and lymph node metastasis in cervical cancer. Furthermore, we provided evidence that NEK2-depleted cervical cancer cells exhibit impaired oncogenesis and enhanced radiosensitivity. Using RNA sequencing, we identify Wnt1 as a key downstream effector of NEK2. Knockdown of NEK2 downregulates the mRNA and protein levels of Wnt1, thereby inhibiting the activation of the Wnt/β-catenin signaling pathway. More importantly, the observed consequences induced by NEK2 depletion in cervical cancer cells can be partially rescued by Wnt1 overexpression. Taken together, these results demonstrate that NEK2 activates the Wnt/β-catenin signaling pathway via Wnt1 to drive oncogenesis and radioresistance in cervical cancer, indicating that NEK2 may be a promising target for the radiosensitization of cervical cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE148531 | GEO | 2021/04/30

REPOSITORIES: GEO

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Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer

Project description:Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer

| PRJNA624895 | ENA

Dose-dependent and subset-specific regulation of midbrain dopaminergic neuron differentiation by LEF1-mediated WNT1/b-Catenin signaling

Project description:The development of the mesodiencephalic dopaminergic (mdDA) neurons strongly depends on the WNT1/b-catenin signaling pathway. These neurons include the Substantia nigra pars compacta (SNc) subset that preferentially degenerates in Parkinson’s Disease (PD), and the ventral tegmental area (VTA) subpopulation implicated in a variety of neuropsychiatric disorders. The identity of the cells responding to this signaling pathway in the developing mammalian ventral midbrain (VM) and the precise mechanism of WNT/b-catenin action in these cells, however, are still unknown. Moreover, this signaling pathway has to be accurately balanced during mdDA neuron development: whereas low levels or absence of WNT1/b-catenin signaling abolish their correct specification, constitutive activation of this signaling pathway prevents their proper differentiation in the mouse. We show that the WNT/b-catenin-responsive cells constitute only a fraction of all mdDA progenitors, precursors and neurons in the murine VM. These WNT/b-catenin-responsive cells are mostly located in the Wnt1+, Rspo2+ and Lef1+ lateral floor plate of the medial and caudal midbrain, giving preferentially rise to caudomedial (VTA) mdDA neurons. Strong WNT/b-catenin signaling mediated by RSPO2, a WNT/b-catenin agonist, and LEF1, a nuclear effector of this pathway, inhibits the differentiation of WNT/b-catenin-responsive mdDA progenitors into mature mdDA neurons by repressing the murine Pitx3 gene via conserved LEF1/TCF binding sites in its promoter. Our data indicate that an attenuation of WNT/b-catenin signaling in mdDA progenitors is essential for their correct differentiation into specific mdDA neuron subsets, thus providing a new means for stem cell-based regenerative therapies of PD and in vitro models of neuropsychiatric diseases.

2020-09-02 | GSE99618 | GEO

NEK2 regulates triple negative breast cancer transcriptome.

Project description:NEK2 is a mitotic kinase that is upregulated and mislocalized in the nucleus of human cancer cells. NEK2 modulates expression and activity of both transcription and splicing factors in cancer cells, nevertheless whether this kinase affects transcriptome regulation genome widely and whether this activity concurs to its oncogenic activity is still unknown. Herein, by high-throughput RNA sequencing analysis of MDA-MB-231 cells transiently silenced for NEK2 we uncover an extensive modulation of triple-negative breast cancer cell transcriptome by this kinase.

2021-12-21 | GSE140803 | GEO

LC-MS proteomics quantitative analysis of pancreatic cancer cells overexpressing NEK2

Project description:The NEK2 overexpression in pancreactic cancer cell (SW1990), and we performed LC-MS to further investigate the manner in which NEK2 regulates PD-L1.

2021-06-29 | PXD026877 | Pride

Transcription profiling of human bone marrow from primary multiple myeloma patients

Project description:Drug resistance is a major obstacle in cancer therapy. The molecular mechanisms of drug resistance still remain largely elusive. Microarray analyses on paired primary myeloma samples at baseline and after therapy or at relapse showed that NEK2 was one of the most up-regulated genes in myeloma cells after high-dose chemotherapy or at relapse. By analyzing the published (> 2,500) microarrays and clinical datasets, we found that NEK2 expression is increased in many malignancies, and that high expression of NEK2 was associated with a shorter event-free and overall survival. Moreover, NEK2 expression was typically increased in tumors with aggressive subtype and advanced TNM stage. Our studies indicate that over-expressing NEK2 in cancer cells resulted in enhanced cell proliferation and drug resistance, whereas knockdown of NEK2 induced significant cancer cell death and growth inhibition. We found that NEK2 over-expression activates cell cycle progression and cell division through the stimulation of cell cycling genes CDC2/CCNB1 and PBK. Interestingly, NEK2-overexpression also activated the Wnt/Î²-catenin signaling pathway. We conclude that NEK2 represents a predictor for drug resistance and poor prognosis in cancers and could be a potential target for cancer therapy. Experiment Overall Design: Myeloma tumor cells from bone marrow aspirates were collected at baseline and after chemotherapy (pre-1st and pre-2nd bone marrow transplant, and pre-consolidation) for RNA extraction and hybridization on Affymetrix microarrays. We sought to define genes related to chemotheraputic resistance.

2010-01-30 | E-GEOD-19554 | biostudies-arrayexpress

wnt1-induced mammary tumor from Rarb KO mice vs. those from Rarb wt (control)

Project description:Previously we have demonstrated that inactivation of retinoic acid receptor beta (Rarb) in the mouse results in a protective effect against ErbB2-induced mammary gland tumorigenesis although Rarb has been reported as a tumor suppressor before. In the current study, we further confirmed that ablation of Rarb has a very similar impact on Wnt1-induced mammary gland tumorigenesis as those on ErbB2-induced mammary gland tumorigenesis. Nevertheless, the mechanisms by which Rarb confers its effects on tumor progression is quite different although both involving in tumor microenvironment (TME) remodeling. In the Wnt1 tumors, ectopic wnt1 produced by malignant luminal cells activates nearby stromal cells by a paracrine manner. In return, the stromal cells secreted IGF1 to regulate the growth of tumor cells. There is a need of Rarb expression in this interaction. Deletion of Rarb inhibits both wnt1/β-catenin signaling and IGF1/Akt axis in the myoepithelial tumor cells which results in the suppression of epithelial-mesenchymal transition (EMT) in these tumors. Since wnt1 tumors resemble basal-like breast cancer with a poor clinical prognosis in which EMT is one of the most important way for tumor cells to survive against standard treatment and to go to metastasis, we propose that (1) the stromal gene expression signature of Rarb ablation in wnt1 tumors could have some clinical value in predicting the breast cancer outcome; and (2) Rarb antagonist might be a potential therapeutic strategy in EMT-driven aggressive cancers such as basal-like breast cancer. Laser capture microdissection (LCM) was performed to separate the mammary tumor samples into epithelial cell compartment and stromal cell compartment. Transcriptional profiling of the two compartments were investigated by microarray analysis.

2014-10-23 | E-GEOD-56391 | biostudies-arrayexpress

Wnt1 silences CC/CXC motif chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma

Project description:Lung adenocarcinoma (LUAD)-derived oncogenic Wnts increase cancer cell proliferative/stemness potential, but whether they also impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. Wnt1 correlated strongly with tolerogenic genes on the TCGA expression data. In another cohort, Wnt1 was inversely associated with T cell abundance. Altering Wnt1 expression profoundly affected growth of murine lung adenocarcinomas and this was strongly dependent on conventional dendritic cells and T cells. Mechanistically, Wnt1 lead to transcriptional silencing of CC/CXC chemokines in dendritic cells and T cell cross-tolerance. Wnt-target genes were up-regulated in human intratumoral dendritic cells and decreased upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-loaded nanoparticles as single therapy or part of combinatorial immunotherapies acted at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 enhances adaptive immune rejection of lung adenocarcinomas and highlight its potential targeting as a novel therapeutic strategy

2018-12-21 | GSE124199 | GEO

Expression data from bone marrow of primary multiple myeloma patients

Project description:Drug resistance is a major obstacle in cancer therapy. The molecular mechanisms of drug resistance still remain largely elusive. Microarray analyses on paired primary myeloma samples at baseline and after therapy or at relapse showed that NEK2 was one of the most up-regulated genes in myeloma cells after high-dose chemotherapy or at relapse. By analyzing the published (> 2,500) microarrays and clinical datasets, we found that NEK2 expression is increased in many malignancies, and that high expression of NEK2 was associated with a shorter event-free and overall survival. Moreover, NEK2 expression was typically increased in tumors with aggressive subtype and advanced TNM stage. Our studies indicate that over-expressing NEK2 in cancer cells resulted in enhanced cell proliferation and drug resistance, whereas knockdown of NEK2 induced significant cancer cell death and growth inhibition. We found that NEK2 over-expression activates cell cycle progression and cell division through the stimulation of cell cycling genes CDC2/CCNB1 and PBK. Interestingly, NEK2-overexpression also activated the Wnt/β-catenin signaling pathway. We conclude that NEK2 represents a predictor for drug resistance and poor prognosis in cancers and could be a potential target for cancer therapy.

2013-01-22 | GSE19554 | GEO

NEK2 regulates triple negative breast cancer transcriptome.

Project description:NEK2 regulates triple negative breast cancer transcriptome.

| PRJNA590988 | ENA

Effect of NEK2 deficiency on gene expression of CD19-selected spleen B cells of Eμ-myc mouse model

Project description:NEK2 overexpression in the B cell lineage affects B cell development. To determine whether deficiency of NEK2 inhibits B cell malignancies, we crossed Nek2 knockout mice with Eμ-myc transgenic mice, a well-established Myc-driven preclinical model for B cell malignancies. Three genotyping offsprings were obtained: Eμ-myc/Nek2+/+ (NEK2 wild type), Eμ-myc/Nek2+/- (NEK2 heterozygotes), and Eμ-myc/Nek2-/- (NEK2 homozygotes). Bulk RNA-seq was performed on CD19-selected spleen B cells to view the transcriptome differences.

2023-06-01 | GSE226675 | GEO

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