Project description:MTA1, SOX4, EZH2 and TGF-β are all potent inducers of epithelial-mesenchymal transition (EMT) in cancer; however, the signaling relationship among these molecules in EMT is poorly understood. Here, we investigated the function of MTA1 in cancer cells and demonstrated that MTA1 overexpression efficiently activates EMT. This activation resulted in a significant increase in the migratory and invasive properties of three different cancer cell lines through a common mechanism involving SOX4 activation, screened from a gene expression profiling analysis. We showed that both SOX4 and MTA1 are induced by TGF-β and both are indispensable for TGF-β-mediated EMT. Further investigation identified that MTA1 acts upstream of SOX4 in the TGF-β pathway, emphasizing a TGF-β-MTA1-SOX4 signaling axis in EMT induction. The histone methyltransferase EZH2, a component of the polycomb (PcG) repressive complex 2 (PRC2), was identified as a critical responsive gene of the TGF-β-MTA1-SOX4 signaling in three different epithelial cancer cell lines, suggesting that this signaling acts broadly in cancer cells in vitro. The MTA1-SOX4-EZH2 signaling cascade was further verified in TCGA pan-cancer patient samples and in a colon cancer cDNA microarray, and activation of genes in this signaling pathway predicted an unfavorable prognosis in colon cancer patients. Collectively, our data uncover a SOX4-dependent EMT-inducing mechanism underlying MTA1-driven cancer metastasis and suggest a widespread TGF-β-MTA1-SOX4-EZH2 signaling axis that drives EMT in various cancers. We propose that this signaling may be used as a common therapeutic target to control epithelial cancer metastasis. We used microarrays to detect MTA1-regulated genes in cancer cells.
Project description:We found that ERY974 shows only moderate antitumor efficacy in NCI-H446 non-inflamed tumor in huNOG mice. We also observed that ERY974 + cisplatin increases antitumour efficacy in non-inflamed NCI-H446 tumours. To identify a mechanism of combination effect, we compared RNA expression of NCI-H446 tumors treated with ERY974, cisplatin, or combination.
Project description:We found that ERY974 shows only moderate antitumor efficacy in NCI-H446 non-inflamed tumor in huNOG mice. We also observed that ERY974 + paclitaxel increases antitumour efficacy in non-inflamed NCI-H446 tumours. To identify a mechanism of combination effect, we compared RNA expression of NCI-H446 tumors treated with ERY974, cisplatin, or combination.
Project description:Mta1 gene expression reveals new targets and functions. Mta1 functions in p53 dependent and independent manner. Genes regulated by Mta1 in the presence and absence of p53 were indetified This expression data contains 5 different samples (MEFs) 1.wild type 2. Mta1 knockout 3. Mta1 re-expression in the knock out MEFs 4. P53 knockout and 5. Mta1 over expression in P53 knock out MEFs. Various sample comparisons were done and genes with p-value< 0.05 and fold change M-bM-^IM-% 2.0 were considered statistically significant 5 samples (triplicates of each, total 15) were analyzed. We generated pairwise comparisons between the WT vs Mta1-KO; Mta1-KO vs Mta1-KO/Mta1; P53-KO vs P53-KO/Mta1.
Project description:Background:
The National Cancer Institute Surgery Branch (NCI-SB) has developed experimental therapies that involve taking white blood cells from patients’ tumor or from their blood, growing them in the laboratory in large numbers, and then giving the cells back to the patient.
Objective:
This study will allow patients to under screening and evaluation for participation in NC-SB Protocols.
Eligibility:
Patients 18 years or older must meet the minimum eligibility criteria for an NCI-SB treatment protocol.
Design
Patients will undergo testing and evaluations as required by the appropriate NCI-SB treatment protocol.
Project description:Mta1 gene expression reveals new targets and functions. Mta1 functions in p53 dependent and independent manner. Genes regulated by Mta1 in the presence and absence of p53 were indetified This expression data contains 5 different samples (MEFs) 1.wild type 2. Mta1 knockout 3. Mta1 re-expression in the knock out MEFs 4. P53 knockout and 5. Mta1 over expression in P53 knock out MEFs. Various sample comparisons were done and genes with p-value< 0.05 and fold change ≥ 2.0 were considered statistically significant
Project description:Little has been known about the genome-wide methylation frameworks of the chemo-resistant cells of SCLC currently, which might provide prospective layouts to discover the genes and the signal pathways related with chemo-resistance of SCLC. Thus, this research reported for the first time the genome-wide abnormal methylation pattern of chemo-resistant H446/DDP cells of human SCLC induced by the cisplatin