Knockdown of DKK3 decreases malignant property in head and neck squamous cell carcinoma-derived HSC-3 cells.
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ABSTRACT:
PROVIDER: PRJNA420015 | ENA |
REPOSITORIES: ENA
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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:We hypothesized that DKK3 may exert oncogenic function supecifically in head and neck squamous cell carcinoma (HNSCC). DKK3 overexpression in HNSCC cell resulted in elevated cellular proliferation, migration, invasion and in vivo tumor growth. This elevated malignant properties was not driven by Wnt/beta-catenin pathway.
2017-07-22 | GSE84725 | GEO
Project description:DKK3 overexpression increases malignant property in head and neck squamous cell carcinoma-derived HSC-3 cells.
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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:Pancreatic ductal adenocarcinoma (PDAC) is characterized by its intricate tumor biology complicated by the spatiotemporal dynamics in the expression and function of specific proteins driving such biology. Here, we employ a mouse model with homozygous and heterozygous DKK3 knockout together with pancreas-specific expression of KRASG12D (DDKC,DKC,KC) to investigate the compartment- and time-dependent roles of DKK3. Our findings demonstrate that DKK3 functions to inhibit oncogenesis during the early stages of cancer while paradoxically promoting tumor progression in the later stages. DDKC and DKC mice exhibited significantly shorter lifespans compared to KC mice, with a higher incidence of high-grade, desmoplastic, “cold” and metastatic cancers. Accordingly, DKK3-deficient acinar cells exhibited a marked increase in acinar-to-ductal-metaplasia, accompanied by increased MAPK-signaling with enhanced expression of the immediate-early genes cfos and Jun. Treatment with the MEK-inhibitor trametinib preserved acinar integrity in DKK3-null pancreata. Additionally, FOS-inhibition restricted the migratory capabilities of DDKC cancer cells. Throughout the progression of mouse and human PDAC, DKK3 expression shifted from epithelial cells to the stromal compartment by the endpoint. DKK3-null tumor cells displayed enhanced migratory abilities when exposed to recombinant DKK3. In line, DKK3-expressing cancer-associated fibroblasts (CAFs) emerged as crucial contributors to this tumor aggressiveness. Orthotopic transplantation studies revealed that DKK3 expression within CAFs promotes tumor growth and fibrosis, particularly in aggressive DDKC tumors. Collectively, these findings highlight the complex and context-dependent role of DKK3 in PDAC, suggesting that it may serve as a promising therapeutic target for the management of this challenging malignancy.
2026-01-21 | GSE283238 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by its intricate tumor biology complicated by the spatiotemporal dynamics in the expression and function of specific proteins driving such biology. Here, we employ a mouse model with homozygous and heterozygous DKK3 knockout together with pancreas-specific expression of KRASG12D (DDKC,DKC,KC) to investigate the compartment- and time-dependent roles of DKK3. Our findings demonstrate that DKK3 functions to inhibit oncogenesis during the early stages of cancer while paradoxically promoting tumor progression in the later stages. DDKC and DKC mice exhibited significantly shorter lifespans compared to KC mice, with a higher incidence of high-grade, desmoplastic, “cold” and metastatic cancers. Accordingly, DKK3-deficient acinar cells exhibited a marked increase in acinar-to-ductal-metaplasia, accompanied by increased MAPK-signaling with enhanced expression of the immediate-early genes cfos and Jun. Treatment with the MEK-inhibitor trametinib preserved acinar integrity in DKK3-null pancreata. Additionally, FOS-inhibition restricted the migratory capabilities of DDKC cancer cells. Throughout the progression of mouse and human PDAC, DKK3 expression shifted from epithelial cells to the stromal compartment by the endpoint. DKK3-null tumor cells displayed enhanced migratory abilities when exposed to recombinant DKK3. In line, DKK3-expressing cancer-associated fibroblasts (CAFs) emerged as crucial contributors to this tumor aggressiveness. Orthotopic transplantation studies revealed that DKK3 expression within CAFs promotes tumor growth and fibrosis, particularly in aggressive DDKC tumors. Collectively, these findings highlight the complex and context-dependent role of DKK3 in PDAC, suggesting that it may serve as a promising therapeutic target for the management of this challenging malignancy.
2026-01-21 | GSE307602 | GEO
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:Immortalized (hpv-E6) murine fibroblasts isolated from normal mammary glands and carcinoma stages (CAFs) from the MMTV-PyMT model (FVB/N background) were used in this analysis. CAFs were transfected with two independent RNAi targeting Dickkopf-3 (DKK3) or control RNAi and changes in whole-genome gene expression were evaluated by microarray. In addition, the effect of stable ectopic expression of DKK3 in normal fibroblasts (which normally do not express DKK3) was also evaluated. Analysis demonstrated the role of DKK3 in controlling specific transcriptional programs in CAFs.
2018-05-05 | GSE114056 | GEO
Project description:Chronic inflammation decreases HSC fitness via hyperactivation of the druggable IL-6/Jak/Stat3 signaling pathway.
| PRJEB47643 | ENA
Project description:the RNA binding property of FSCN1
| PRJNA811187 | ENA