Erratum: Variations in the Wnt/?-Catenin Pathway Key Genes as Predictors of Cervical Cancer Susceptibility [Corrigendum].
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PROVIDER: S-EPMC7457665 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Erratum: Variations in the Wnt/β-Catenin Pathway Key Genes as Predictors of Cervical Cancer Susceptibility [Corrigendum].
Pharmacogenomics and personalized medicine 20200824
[This corrects the article DOI: 10.2147/PGPM.S248548.]. ...[more]
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Project description:BackgroundCervical cancer is the fourth most common and fatal tumor among women worldwide. The Wnt/β-catenin signaling pathway was etiologically involved in the cervical cancer model. Herein, we aimed to investigate whether germline genetic variations within the Wnt/β-catenin pathway can be genetic risk factors of cervical cancer.Patients and methodsA total of 305 samples (147 patients, 158 controls) were included. Eight genetic variations located in APC (rs454886), GSK3β (rs3755557), CTNNB1 (rs11564475, rs1798802, rs3864004, rs2293303, and rs4135385), and TCF7L2 (rs7903146) were genotyped via Sanger sequencing. The χ 2 test and non-conditional logistic regression were used in the single-locus analysis. Gene-gene interactions and haplotype construction in case-control samples were performed by the GMDR method and Haploview software, respectively.ResultsThe frequency of CTNNB1 rs1798802 GA+AA genotype was significantly lower in cervical cancer patients adjusted for age (OR=0.626, 95% CI=0.398-0.984). The mutant alleles of rs3864004 (A) and rs2293303 (T) located in CTNNB1 showed 1.513 (1.038-2.207), and 1.654 (1.020-2.683) fold increased risk of cervical cancer, respectively. Haplotype analysis showed no association between haplotypes of the CTNNB1 gene and cervical cancer risk. No significant contribution of interactions among genes in the Wnt pathway was identified.ConclusionWe concluded that the genetic variants in the CTNNB1 gene might contribute to the development of cervical cancer.
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Project description:[This corrects the article DOI: 10.1111/eva.13176.].
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Project description:Excessive activation of the Wnt signalling pathway in the articular cartilage is demonstrated to be related to the onset and severity of osteoarthritis (OA). However, few studies have investigated the association between variants in Wnt-pathway-related genes and the risk of OA by searching Pubmed and EMBASE. Totally, 471 knee OA patients and 532 controls were recruited from three hospitals to evaluate the associations of five genetic variants (rs61735963, rs2908004, rs10795550, rs1799986 and rs1127379) with the risk of knee OA. These polymorphisms were genotyped through polymerase chain reaction and Sanger sequencing. Genetic risk scores (GRSs) were calculated to evaluate the combined effect of these genetic variants. No significant association was found between OA risk and polymorphisms (rs61735963, rs10795550 or rs1127379). However, WNT16 rs2908004 polymorphism was correlated with a decreased risk of OA, especially among females, smokers, non-drinkers and individuals with age < 60 years or BMI ≥ 25. This SNP was also associated with Kellgren-Lawrence grade and CRP. Similarly, LRP1 rs1799986 polymorphism decreased the risk of OA among males, smokers, drinkers and individuals with age < 60 years or BMI ≥ 25. TT genotype was more frequent in the group of VAS ≥ 6 versus VAS < 6. A low GRS was positively correlated with a decreased risk of OA. In addition, rs2908004 or rs1799986 polymorphism reduces the expression of WNT16 or LRP1. In conclusion, two SNPs (rs2908004 and rs1799986) are associated with the decreased risk of OA by regulating the Wnt pathway.
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Project description:BackgroundKIF18B was identified as a potential oncogene by analysis of The Cancer Genome Atlas database.Materials and methodsWe assessed KIF18B expression and explored its clinical significance in cervical cancer tissues. We have also evaluated the effects of KIF18B on cervical cancer cell proliferation, migration, and invasion both in vitro and in vivo.ResultsOur results show that KIF18B is overexpressed in cervical cancer tissues and is associated with a large primary tumor size, an advanced FIGO stage, and an advanced tumor grade. Knockdown of KIF18B induces cell cycle G1-phase arrest and inhibits the proliferation, migration, and invasion of cervical cancer cells, whereas its overexpression promotes proliferation, migration, and invasion in these cells. Moreover, silencing of KIF18B reduces expression of CyclinD1, β-catenin, C-myc, and p-GSK3β expression.ConclusionThese data suggest that KIF18B can serve as a novel oncogene that promotes the tumorigenicity of cervical cancer cells by activating Wnt/β-catenin signaling pathway.
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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.
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Project description:The bioflavonoid apigenin has been shown to possess cancer-preventive and anti-cancer activities. In a drug screening, we found that apigenin can inhibit Wnt/β-catenin signaling, a pathway that participates in pivotal biological functions, which dis-regulation results in various human diseases including cancers. However, the underlying mechanism of apigenin in this pathway and its link to anti-cancer activities remain largely unknown. Here we showed that apigenin reduced the amount of total, cytoplasmic, and nuclear β-catenin, leading to the suppression in the β-catenin/TCF-mediated transcriptional activity, the expression of Wnt target genes, and cell proliferation of Wnt-stimulated P19 cells and Wnt-driven colorectal cancer cells. Western blotting and immunofluorescent staining analyses further revealed that apigenin could induce autophagy-mediated down-regulation of β-catenin in treated cells. Treatment with autophagy inhibitors wortmannin and chloroquine compromised this effect, substantiating the involvement of autophagy-lysosomal system on the degradation of β-catenin during Wnt signaling through inhibition of the AKT/mTOR signaling pathway. Our data not only pointed out a route for the inhibition of canonical Wnt signaling through the induction of autophagy-lysosomal degradation of key player β-catenin, but also suggested that apigenin or other treatments which can initiate this degradation event are potentially used for the therapy of Wnt-related diseases including cancers.
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Project description:Human papillomavirus type 18 (HPV18) has high carcinogenic power in invasive cervical cancer (ICC) development. However, the underlying mechanism remains elusive. The carcinogenic properties of HPV18 require the PDZ-binding motif of its E6 oncoprotein (HPV18 E6) to degrade its target PSD95/Dlg/ZO-1 (PDZ) proteins. In this study, we demonstrated that the PDZ protein membrane-associated guanylate kinase, WW and PDZ domain containing 3 (MAGI3) inhibited the Wnt/β-catenin pathway, and subsequently cervical cancer (CC) cell migration and invasion, via decreasing β-catenin levels. By reducing MAGI3 protein levels, HPV18 E6 promoted CC cell migration and invasion through activation of Wnt/β-catenin signaling. Furthermore, HPV18 rather than HPV16 was preferentially associated with the downregulation of MAGI3 and activation of the Wnt/β-catenin pathway in CC. These findings shed light on the mechanism that gives HPV18 its high carcinogenic potential in CC progression.
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Project description:The SRY-box containing gene 17 (SOX17) is considered as a regulator in stemness maintenance and a suppressor in some malignant tumors. However, the biological function and molecular mechanism of SOX17 in the process of initiation and progression of cervical cancer remain obscure. In this study, immunohistochemistry showed that the expression of SOX17 was high in the normal cervix, moderate in the high-grade squamous intraepithelial lesion, and low in the cervical cancer. SOX17 inhibited the proliferation and viability of cervical cancer cells in vitro as well as tumor formation in vivo. Additionally, SOX17 induced the cell cycle arrest at the transition from the G0/G1 phase to the S phase. The TOP/ FOP-Flash reporter assay and Western blotting showed SOX17 inhibited the activity of the Wnt/β-catenin signaling pathway in cervical cancer. Further, firefly luciferase reporter assay and quantitative chromatin immunoprecipitation (qChIP) assays confirmed that SOX17 trans-suppressed the expression of β-catenin by directly binding to the specific region of the β-catenin promoter. Together, our data demonstrated that SOX17 restrained the proliferation and tumor formation by down-regulating the activity of the Wnt/β-catenin signaling pathway via trans-suppression of β-catenin in cervical cancer.
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Project description:Transcriptional factor 3 (TCF3, also termed E2A), first reported to exert crucial functions during lymphocyte development, has been revealed to participate in the pathogenesis of human cancers. The aim of this work was to investigate the function of TCF3 in cervical cancer (CC) and the molecular interactions. The bioinformatics prediction suggested that TCF3 was highly expressed in CC and linked to poor prognosis. Increased TCF3 expression was identified in CC cell lines, and its downregulation reduced proliferation and migration of CC cells in vitro as well as growth of xenograft tumors in vivo. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses showed that the TCF-3-related genes and genes showed differential expression between CC and normal tissues were mainly enriched in the Wnt/β-catenin pathway. TCF3 bound to sirtuin 1 (SIRT1) promoter for transcriptional activation, and SIRT1 promoted deacetylation and nuclear translocation of β-catenin in CC. SIRT1 overexpression blocked the role of TCF3 silencing and restored cell proliferation in vitro and tumor growth in vivo. Treatment with XAV-939, a β-catenin inhibitor, significantly suppressed the cell proliferation and tumor growth induced by SIRT1 overexpression. In conclusion, this study demonstrates that TCF3 augments progression of CC by activating SIRT1-mediated β-catenin signaling.
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Project description: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/β-catenin pathway was significantly inactivated in DAX1-silenced cervical cancer cells with the downregulation of Wnt/β-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 3β (GSK3β), an inhibitor of the Wnt/β-catenin pathway, by physically interacting with -666~-444 motif on the GSK3β promoter. Additionally, the blockage of GSK3β 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/β-catenin pathway mediated by GSK3β.
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