Role for TNFAIP2: Relationships with Outcomes and EMT in Urothelial Cancers under the Control of Cisplatin
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ABSTRACT:
PROVIDER: PRJNA484932 | ENA |
REPOSITORIES: ENA
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Project description:Background: Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many cancer types. However, the phenotypic hallmark of tumors often changes after CDDP, with the acquisition of Epithelial-to-mesenchymal transition (EMT) and platinum resistance. Yet, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Methods: Following an investigation of urothelial cancers (UCs) before and after the acquisition of platinum resistance, we offered the new target TNFAIP2, which led to EMT and tumor invasion. TNFAIP2 expression in cancers were examined at the protein and transcription levels. Results: Clinically, up-regulated TNFAIP2 expression was identified as a significant predictor of mortality in upper urinary tract UCs. TNFAIP2 knockdown resulted in up-regulated E-cadherin expression and down-regulated TWIST expression in cancers, which decreased motile function. TNFAIP2 overexpression led to down-regulated E-cadherin expression and up-regulated TWIST expression. Clinical investigations on matched pre- and post-CDDP-treated sections confirmed up-regulated TNFAIP2 expression in CDDP-treated tumors, but down-regulated E-cadherin expression. A global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition. Conclusions: Our results suggest a relationship between TNFAIP2 and EMT in cancers, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.
2018-08-08 | GSE118233 | GEO
Project description:Bladder cancer is a major and mortal disease in urological area. Cisplatin is a key drug for bladder cancer especially for muscle invasive cases. In most cases of bladder cancer, cisplatin is effective; however, resistance to cisplatin is critical for patient’s prognosis. Thus, treatment strategy for cisplatin resistant bladder cancer is essential to improve current prognosis. In this study, we established cisplatin resistant bladder cancer line (CR cells) using a urothelial carcinoma line UM-UC-3 cells. We screened potential targets for CR cells and found that claspin is overexpressed in CR cells. Claspin mRNA knockdown revealed that claspin has a role in cisplatin resistance in CR cells. In our previous study, we found HLA-A*02:01-restricted CLSPN peptide by an HLA ligandome analysis. We thus generated CLSPN peptide specific CTL clone and found that CLSPN peptide-specific CTL clone recognized CR cells at higher levels compared with that of UM-UC-3 wild type cells. These findings indicate that claspin is a driver for cisplatin resistance and claspin peptide-specific immunotherapy is effective for cisplatin resistant cases.
2024-04-10 | GSE217413 | GEO
Project description:Background: The relationships between cancer stem cells (CSCs), epithelial-to-mesenchymal transition (EMT), and the tumor microenvironment (TME) in bladder urothelial carcinoma (BLCA) remain unclear. Methods: We first constructed tumor stemness (TS) score using principal component analysis to quantify tumor stemness in BLCA. Then, we evaluated the clinical value of the TS score for predicting the response to tumor immunotherapy using immunotherapy cohorts. Finally, we built an EMT cell model by treating T24 cells with TGF-β and validated the relationship between the TS score and the EMT process in tumors by real-time quantitative PCR, cell invasion assays, and RNA-seq. Results: A TS scoring system was established with 61 TS-related genes to quantify the TS. The prognostic value of the TS score was then confirmed in multiple independent cohorts. A high TS score was associated with high EMT activity, CSC characteristics, high stromal cell content, high TP53 mutation rate, poor prognosis, and high tumor immunotherapy tolerance. Conclusion: The TS score provides an index for EMT and CSC research and helps clinicians develop treatment plans and predict outcomes for patients.
2022-10-21 | GSE215947 | GEO
Project description:To identify the possible targets in EMT-acquisition after developing acquired platinum resistance in urothelial carcinoma (UC), we examined the changes in global gene expression before and after development of acquired platinum resistance. Comparing two types of acquired platinum resistant UC cells and their corresponding parent cells, in the end we identified 49 genes (25 up-regulated and 24 down-regulated genes) which were commonly changed in two acquired platinum resistant UC cells. Four invasive UC cell lines, T24, 5637, and those acquired platinum-resistant sublines T24PR and 5637PR, were used for microarrays. T24PR and 5637PR cells were newly established in our laboratory, which were grown and passaged upon reaching confluence in medium containing CDDP over a 6-month period. In preliminary studies, we found that these cell lines had an altered phenotype with morphologic and molecular changes consistent with EMT, and exhibited a marked difference in migratory potential before and after developing platinum resistance.
2016-07-01 | E-GEOD-58624 | biostudies-arrayexpress
Project description:To identify the possible targets in EMT-acquisition after developing acquired platinum resistance in urothelial carcinoma (UC), we examined the changes in global gene expression before and after development of acquired platinum resistance. Comparing two types of acquired platinum resistant UC cells and their corresponding parent cells, in the end we identified 49 genes (25 up-regulated and 24 down-regulated genes) which were commonly changed in two acquired platinum resistant UC cells.
2016-07-01 | GSE58624 | GEO
Project description:In this study we transfected A549 cells with siRNA against TNFAIP2, infected them with L. pneumophila and performed transcriptional profiling. We found enrichment of genes in pro-inflammatory pathways by Pathway Over-respresentation analysis upon infection. There was no significant change in gene expression that we could attribute specifically to the knockdown of TNFAIP2. Examination of the transcriptional response of A549 cells to Legionella infection with concomitant TNFAIP2 knockdown
2016-04-13 | E-GEOD-80214 | biostudies-arrayexpress
Project description:Chemo-resistance to platinum such as cisplatin is critical in the treatment of ovarian cancer. Recent evidences have linked epithelial-mesenchymal transition (EMT) with the drug resistance as a contributing mechanism. The current study explored the connection between cellular responses to cisplatin with EMT in ovarian cancer. 46 ovarian carcinoma cell lines expression data with and without Cisplatin treatment.
2014-07-29 | E-GEOD-47856 | biostudies-arrayexpress
Project description:The Phase 3 1L urothelial carcinoma (IMvigor130) trial revealed more favorable effects on overall survival with atezolizumab combined with gemcitabine and cisplatin (GemCis) than with atezolizumab combined with gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin vs carboplatin as a potential explanation for these clinical observations. GemCis compared with GemCarbo ± atezolizumab induced transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T-cell activation programs. In vitro experiments demonstrated that cisplatin, compared with carboplatin, exerted direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in urothelial carcinoma and highlight the potential importance of specific chemotherapy backbones for immune checkpoint blockade combination therapies.
2023-11-02 | GSE235066 | GEO
Project description:Lipid metabolism is recognized as a key process for stem cell maintenance and differentiation but genetic factors that instruct stem cell function by influencing lipid metabolism remain to be delineated. Here we identify Tnfaip2 as an inhibitor of reprogramming of mouse fibroblasts into induced pluripotent stem cells. Tnfaip2 knockout embryonic stem cells (ESCs) exhibit differentiation failure and knockdown of the planarian orthologue, Smed-exoc3, abrogates in vivo differentiation of somatic stem cells, tissue homeostasis, and regeneration. Tnfaip2 deficient ESCs fail to induce synthesis of cellular triacylglycerol (TAG) and lipid droplets (LD) coinciding with reduced expression of Vimentin (Vim) – a known inducer of LD formation. Knockdown of Vim and Tnfaip2 act epistatically in enhancing cellular reprogramming of mouse fibroblasts. Similarly, planarians devoid of Smed-exoc3 displayed acute loss of TAGs. Supplementation of palmitic acid (PA) and palmitoyl-L-carnitine (a mitochondrial carrier of PA) restores the differentiation capacity of Tnfaip2 deficient ESCs as well as stem cell differentiation and organ maintenance in Smed-exoc3-depleted planarians. Together, these results identify a novel pathway, which is essential for stem cell differentiation and organ maintenance by instructing lipid metabolism.
2020-11-16 | GSE134300 | GEO
Project description:Chemo-resistance to platinum such as cisplatin is critical in the treatment of ovarian cancer. Recent evidences have linked epithelial-mesenchymal transition (EMT) with the drug resistance as a contributing mechanism. The current study explored the connection between cellular responses to cisplatin with EMT in ovarian cancer.
2014-07-29 | GSE47856 | GEO