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DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/?-catenin pathway via GSK3?.

ABSTRACT: DAX1 is well known for its fundamental role in several types of cancer, while its biological role in cervical cancer remains largely unexplored. The expression of DAX1 in cervical carcinoma tissue was examined using immunohistochemistry and western blot. The effects of DAX1 silencing on the cell growth, tumor formation, and CSC (cancer stem cell) characteristics were also investigated. DAX1 expressed a gradual increase from normal cervix to high-grade squamous intraepithelial lesions, and consequently to cervical cancer. Silence of DAX1 significantly inhibited the cell growth, tumorigenicity, and tumorsphere formation. Furthermore, the TOP/FOP-Flash reporter assay revealed that Wnt/?-catenin pathway was significantly inactivated in DAX1-silenced cervical cancer cells with the downregulation of Wnt/?-catenin targeting genes, including cyclinD1 and c-myc. Moreover, dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assay confirmed that DAX1 transcriptionally repressed glycogen synthase kinase 3? (GSK3?), an inhibitor of the Wnt/?-catenin pathway, by physically interacting with -666~-444 motif on the GSK3? promoter. Additionally, the blockage of GSK3? by CHIR-99021 resulted in a significant increase of CSC characteristics induced by the silence of DAX1. Our data demonstrated that DAX1 is overexpressed in cervical cancer, and that it promotes cell growth and tumorigenicity through activating Wnt/?-catenin pathway mediated by GSK3?.

SUBMITTER: Liu XF

PROVIDER: S-EPMC5832878 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/β-catenin pathway via GSK3β.

Liu Xiao-Fang XF Li Xue-Yuan XY Zheng Peng-Sheng PS Yang Wen-Ting WT

Cell death & disease 20180301 3

DAX1 is well known for its fundamental role in several types of cancer, while its biological role in cervical cancer remains largely unexplored. The expression of DAX1 in cervical carcinoma tissue was examined using immunohistochemistry and western blot. The effects of DAX1 silencing on the cell growth, tumor formation, and CSC (cancer stem cell) characteristics were also investigated. DAX1 expressed a gradual increase from normal cervix to high-grade squamous intraepithelial lesions, and conseq ...[more]

PMID: 29497051

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Project description:BackgroundStudies have shown that cancer susceptibility candidate 11 (CASC11), a newly discovered long non-coding RNA (lncRNA), was aberrantly overexpressed in hepatic carcinoma, gastric cancer and colorectal cancer. However, its effects on cervical cancer has been kept unknown up to now. The present study was aimed to investigate the relationship between lncRNA CASC11 and cervical cancer and further explore the mechanism of CASC11 effect on cervical cancer progression.MaterialsQuantitative real-time polymerase chain reaction (RT-qPCR) was used to detect the expressions of CASC11 in cancerous and adjacent normal tissues of patients with cervical cancer as well as in cell lines. The proliferation, migration, invasion and apoptosis were assayed after transfecting the cell with si-CASC11 or pcDNA3.1-CASC11. TOP/FOP-Flash luciferase reporter assay and western blot were used to analysis the activation of Wnt/β-catenin signaling pathway. Si-CASC11-transfected HeLa cells were subcutaneously inoculated into male athymic (nude) mice to investigate the effect of CASC11 on the tumor formation.ResultsWe discovered that CASC11, the expression of which was positively associated with the tumor size and the FIGO staging and negatively related to the patients' survival rate, was up-regulated in the cervical cancer tissues and cell lines. Silencing CASC11 inhibited the proliferation, migration as well as invasion and promoted the cell apoptosis. Conversely, overexpression of CASC11 facilitated the cancer cell's proliferation, migration and invasion ability and suppressed the apoptosis. Further study showed that CASC11 promoted the migration and invasion of cervical cancer cells by activating Wnt/β-catenin signaling pathway and silencing CASC11 inhibited the tumor growth in vivo.ConclusionOur study demonstrated that CASC11 promoted the cervical cancer progression by activating Wnt/β-catenin signaling pathway for the first time, which provides a new target or a potential diagnostic biomarker of the treatment for cervical cancer.

Project description:Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, has recently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis in Trem2-/- mouse brains, induced cell cycle arrest at the G1/S checkpoint, and decreased the stability of β-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes, including cell survival. TREM2 stabilized β-catenin by inhibiting its degradation via the Akt/GSK3β signaling pathway. More importantly, treatment with Wnt3a, LiCl, or TDZD-8, which activates the β-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis in Trem2-/- microglia and/or in Trem2-/- mouse brain. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/β-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.SIGNIFICANCE STATEMENT Mutations in the TREM2 (Triggering Receptor Expressed on Myeloid cells 2) gene are associated with increased risk for Alzheimer's disease (AD) with effective sizes comparable to that of the apolipoprotein E (APOE) ε4 allele, making it imperative to understand the molecular pathway(s) underlying TREM2 function in microglia. Our findings shed new light on the relationship between TREM2/DNAX-activating protein 12 (DAP12) signaling and Wnt/β-catenin signaling and provide clues as to how reduced TREM2 function might impair microglial survival in AD pathogenesis. We demonstrate that TREM2 promotes microglial survival by activating the Wnt/β-catenin signaling pathway and that it is possible to restore Wnt/β-catenin signaling when TREM2 activity is disrupted or reduced. Therefore, we demonstrate the potential for manipulating the TREM2/β-catenin signaling pathway for the treatment of AD.

Dataset Information

DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/?-catenin pathway via GSK3?.

Publications

DAX1 promotes cervical cancer cell growth and tumorigenicity through activation of Wnt/β-catenin pathway via GSK3β.

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