DKK3 overexpression increases malignant property in head and neck squamous cell carcinoma-derived HSC-3 cells.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84725 | GEO | 2017/07/22
SECONDARY ACCESSION(S): PRJNA330950
REPOSITORIES: GEO
Similar Datasets
Project description:We hypothesized that DKK3 may exert oncogenic function supecifically in head and neck squamous cell carcinoma (HNSCC). DKK3 knockdown in HNSCC cell resulted in decreased cellular proliferation, migration, invasion and in vivo tumor growth.
2018-11-30 | GSE107403 | GEO
Project description:Knockdown of DKK3 decreases malignant property in head and neck squamous cell carcinoma-derived HSC-3 cells.
| PRJNA420015 | ENA
Project description:DKK3, a member of the dickkopf Wnt signaling pathway inhibitor family, is believed to be a tumor suppressor because of its reduced expression in cancer cells. However, our previous studies have revealed that DKK3 expression is predominantly observed in head and neck/oral squamous cell carcinoma (HNSCC/OSCC). Interestingly, HNSCC/OSCC patients with DKK3 expression showed a high rate of metastasis and poorer survival, and siRNA-mediated knockdown of DKK3 in HNSCC-derived cancer cell lines resulted in reduced cellular migration and invasion. From these data, it was hypothesized that DKK3 might exert an oncogenic function specific to HNSCC. In the present research, the DKK3 overexpression model was established, and its influences were investigated, together with molecular mechanism studies. The DKK3 expression profile in cancer cell lines was investigated, including HNSCC/OSCC, esophageal, gastric, colorectal, pancreatic, prostatic, and lung cancers. DKK3 overexpression was performed in HNSCC-derived cells by transfection of expression plasmid. The effects of DKK3 overexpression were assessed on cellular proliferation, migration, invasion, and in vivo tumor growth. The molecular mechanism of DKK3 overexpression was investigated by Western blotting and microarray analysis. DKK3 overexpression significantly elevated cellular proliferation, migration, and invasion, as well as increased mRNA expression of cyclin D1 and c-myc. However, reporter assays did not show TCF/LEF activation, suggesting that the increased malignant property of cancer cells was not driven by the Wnt/β-catenin pathway. For the investigation of the pathways/molecules in DKK3-mediated signals, the Western blot analyses revealed that phosphorylation of Akt (S473) and c-Jun (Ser63) was elevated. The application of a PI3K kinase inhibitor, LY294002, on HSC-3 DKK3 cells significantly decreased tumor cell proliferation, migration, and invasion. From these results, we demonstrated that DKK3 might contribute to cellular proliferation, invasion, migration, and tumor cell survival in HNSCC cells through a mechanism other than the canonical Wnt signaling pathway, which might be attributed to PI3K-Akt signaling.
| S-EPMC7844562 | biostudies-literature
Project description:This phase 2 study evaluates the combination of Ad-SGE-Dickkopf-3 (DKK3) gene therapy and nivolumab in patients with chemotherapy-refractory epithelioid malignant pleural mesothelioma (MPM). This clinical study was based on our preclinical study to overcome primary immune resistance by combining Ad-SGE-DKK3 gene therapy with anti-PD-1 therapy through DKK3-driven immune modulation in mesothelioma. The study enrolled 12 patients between 2019 and 2022, who were refractory to pemetrexed-platin-based chemotherapy. Treatment involved CT-guided intratumoral injections of Ad-SGE-DKK3 and systemic nivolumab administration. The primary goal was to assess the objective response rate (ORR), with secondary and exploratory objectives focusing on safety, durable clinical benefit (DCB), survival, and biomarker changes. Of the enrolled patients, 75% completed the Ad-SGE-DKK3 treatment protocol. The study observed a 16.6% ORR with 41.7% maintaining stable disease, which reached 58.3% DCB rate. The median overall survival was 14.5 months, and the median progression-free survival was 4.5 months. Adverse events of grade 3 were noted in 41.7% of patients. Serial analysis of tumor biopsies and serum biomarkers indicated that patients with DCB had increased tumor-infiltrating CD8 T cells, decreased circulating memory CD8 T cells, and sustained lower concentrations of soluble mesothelin and M-CSF than progressors. The combination therapy demonstrated a favorable safety profile and promising efficacy in this patient population. ClinicalTrials.gov identifier: NCT04013334
2024-07-30 | GSE273448 | GEO
Project description:Medulloblastoma (MB) is one of the most common malignant pediatric brain tumor. The aim of our study was to understand which mechanisms are involved in aberrant activation of Wnt pathway and its association with MB tumor development. We studied the expression profiles of 19 MBs tumors using a genome-wide approach, furthermore we have included the data obtained from four independent public Datasets of gene expression (see README file below) to increase the statistical power of the study. The expression profiles identified the Wnt inhibitor gene, DKK3, significant down-regulated. DKK3 down-regulation was confirmed by qPCR in 80% of samples (27/33 MB tumors and in 3/5 MB human cell lines). Since DKK3 was found methylated in several cancers we also investigated the status of methylated CpG sites within the three promoters by a combination of two approaches: the MSP and pyrosequencing. MSP showed no methylation in all promoters while the pyrosequencing, a quantitative technique, indicated a very low level of methylation. To verify the epigenetic involvement on DKK3 silencing, we also studied the effect of Trichostatin A (TSA) in 4 MB cell lines (DAOY; D283; D425; D458). After TSA treatment we observed a significant DKK3 mRNA expression increase in 3/4 cell lines compared to the no treated cells. DAOY cells, that have a normal DKK3 expression value, did not change significantly the DKK3 expression after TSA treatment. To further validate the role of histone tail modifications as an epigenetic silencing mechanism for DKK3 in MB, we performed Chromatin Immunoprecipitation (ChIP) experiment using antibodies against acetylated histones. According to our earlier results, TSA treatment increased the signal of the histone modification meH3K4 which is related to a transcriptionally active gene respect to the untreated controls. Finally, we evaluated the DKK3 protein in three MB cell lines (DAOY; D283; D425) after 24h of TSA treatment, by immunofluorescence.
2013-03-31 | GSE39182 | GEO
Project description:To screen microRNAs (miRNAs) that are deregulated in head and neck squamous cell carcinoma (HNSCC), we comparatively analyzed the miRNA profiles by using 10 HNSCC patient samples and paired adjacent non-cancerous counterparts. Microarray analysis revealed that 24 miRNAs were downregulated and 19 miRNAs were elevated in HNSCC samples when compared with adjacent non-cancerous tissue. These miRNAs included upregulated miR-21-5p, miR-21-3p, and downregulated miR-99a-5p, which have been reported to regulate malignant progression of HNSCC in previous studies.
2020-01-21 | GSE124566 | GEO
Project description:The involvement of microRNAs (miRNAs) in cancer and their potential as biomarkers of diagnosis, prognosis and response to therapy is becoming increasingly appreciated. The etiology of head and neck squamous cell carcinoma (HNSCC) is predominantly associated with the synergistic effects of tobacco and alcohol use, as well as Human Papilloma Virus (HPV) infection, which embodies a distinct clinical and biological phenotype. We sought to examine whether the profile of miRNAs in HNSCC varies based on HPV status, and to identify specific miRNAs altered in head and neck carcinogenesis. Total RNA was isolated from 16 HNSCC fresh frozen primary tumors, 5 fresh frozen non-diseased head and neck epithelial tissues, and 2 HNSCC cell lines. The miRNA profile of 662 individual miRNAs in these tissues was examined by microarray. 18 miRNAs are significantly altered in their expression between normal tissues and HNSCC tumors and 5 miRNAs are identified as significantly differentially expressed between HPV-positive (HPV+) and HPV-negative (HPV-) tumors. A striking difference in expression pattern of miRNA was also observed between primary tissues and cell lines. These data suggest that the pattern of miRNA expression may be reflective of disease etiology, and may be useful in the realm of diagnostic biomarkers defining broadly responsive prevention and treatment strategies for HNSCC. These data also suggest that cultured tumor cell lines may be inappropriate for novel miRNA biomarker identification. Keywords: miRNA; Disease-state analysis Expression of 662 individual miRNA was assessed in16 HNSCC fresh frozen primary tumors, 5 fresh frozen non-diseased head and neck epithelial tissues, and 2 HNSCC cell lines were arrayed
2010-05-19 | E-GEOD-11163 | biostudies-arrayexpress
Project description:This study represents a proteomic resource for HNSCC and SQCLC with quantitative protein expression data for 7800 proteins and provides a proteomic diagnostic signature for classification for undetermined secondary lung tumors in HNSCC patients. By quantitative mass-spectrometry-based proteomics, we characterized a cohort of 63 squamous cell carcinomas of the lung (SQCLC), 49 of the head and neck region (HNSCC) and 51 HNSCC-correlated lung tumors with squamous cell histology that evolved in the course of the disease.
2018-08-06 | PXD007705 | Pride
Project description:Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers in India. Despite improvements in treatment strategy, the survival rates of HNSCC patients remains poor. Thus, it is necessary to identify biomarkers that can be used for early detection of disease. In this study, we employed iTRAQ-based quantitative mass spectrometry analysis to identify dysregulated proteins from a panel of head and neck squamous cell carcinoma (HNSCC) cell lines. We identified 2,468 proteins, of which 496 proteins were found to be dysregulated in at least two HNSCC cell lines compared to immortalized normal oral keratinocytes. We detected increased expression of replication protein A1 (RPA1) and heat shock protein family H (Hsp110) member 1 (HSPH1), in HNSCC cell lines compared to control. The differentially expressed proteins were further validated using parallel reaction monitoring (PRM) and western blot analysis in HNSCC cell lines. Immunohistochemistry-based validation using HNSCC tissue microarrays revealed overexpression of RPA1 and HSPH1 in 15.7% and 32.2% of the tested cases, respectively. Our study illustrates quantitative proteomics as a robust approach for identification of potential HNSCC biomarkers.
2018-09-19 | PXD009241 | Pride
Project description:Head and neck squamous cell carcinoma(HNSCC) is a significant cause of mortality, while the underlying mechanism remains unclear. Recent studies indicate that KIF2C could play a vital role in tumor proliferation and metastasis. Our results demonstrate that KIF2C is highly expressed at both the mRNA and protein levels in HNSCC samples compared to normal samples. Gene ontol-ogy and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that differentially expressed genes were enriched in processes or pathways related to cell adhesion and cell mitosis in HNSCC. Additionally, a protein-protein interaction network was established, identifying KIF2C as a potential hub gene in HNSCC. Cell phenotype assays showed that KIF2C knockdown reduces cell migration and invasion ability and exhibited cell cycle arrest, high proportion of abnormal cell apoptosis and cell chromosome division mismatches in HNSCC cell line. RNA-seq and RT-PCR assay results revealed that KIF2C knockdown influenced the expression levels of PDGFA, CCNA1, RRM1, CCND2, CAV1, EGFR, SNAI2, KRT5, KRT14, NID1, TP63. TGFBR2, TGFB2, ICAM1, ITGB2, CDH2, CDH5, FN1. And KIF2C knockdown also decreased the phos-phorylation of mTOR, AKT, and ERK. Furthermore, in vivo studies have demonstrated that KIF2C knockdown significantly inhibits tumor proliferation in nude mice. As such, our study highlights the potential therapeutic role of KIF2C for HNSCC treatment.
2024-01-21 | GSE253500 | GEO