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Mechanistic Insights into Epithelial-Mesenchymal Transition Mediated Cisplatin Resistance in Ovarian Cancer

ABSTRACT: Mechanistic Insights into Epithelial-Mesenchymal Transition Mediated Cisplatin Resistance in Ovarian Cancer

PROVIDER: PRJNA1112793 | ENA |

REPOSITORIES: ENA

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Mechanistic Insights into Epithelial-Mesenchymal Transition Mediated Cisplatin Resistance in Ovarian Cancer

Project description:Epithelial-mesenchymal transition (EMT) is designated as one of the prime causes of chemoresistance in many cancers. In our previous study we established that cisplatin resistance in ovarian cancer (OC) is associated with EMT using sensitive OV90 cells and its resistant counterparts OV90CisR1 and OV90CisR2. In this study, through RNAseq analysis we revealed that ITGA1 can play essential part in EMT mediated cisplatin resistance in OC. We found large number of EMT related terms predominant in the top gene ontologies (GO). We also found ECM and actin cytoskeleton genes highly altered in the resistant cells. This was further confirmed by the protein-protein interaction (PPI) analysis where we identified that the core ECM components e.g., collagen, fibronectin, metalloproteases and integrins possessed most interactions. The pathway analysis revealed the Wnt signaling as the leading pathway. Since integrins have significant interaction with Wnt signaling, we focused our study on integrins among which, ITGA1, ITGA6, ITGA11 and ITGAV were primarily altered. We validated our results by western blotting and found that ITGA1 was highly expressed in resistant cells. Additionally, the high ABCA5 (efflux transporter) expression in resistant cells also supports the EMT proposition. The western blotting also revealed high β-catenin expression in resistant cells confirming the high Wnt signaling activity. Further, we induced xenograft tumors in nude mice. The histopathological analysis confirmed the aggressive nature of resistant tumors and showed the presence of necrotic core which could be implicated to EMT. Finally, the immunohistochemical staining confirmed the high protein expression in resistant tumor.

2025-01-29 | GSE267752 | GEO

DCBLD2 Mediates Epithelial-Mesenchymal Transition-Induced Metastasis by Cisplatin in Lung Adenocarcinoma

Project description:Growing evidence suggests that cisplatin and other chemotherapeutic agents promote tumor me-tastasis while inhibiting tumor growth, which is a critical issue in clinical practices. However, the role of chemotherapeutics in promoting tumor metastasis and the molecular mechanism involved are unclear. Here, we investigated the roles of cisplatin in promoting tumor metastasis in lung adenocarcinoma (LUAD). We demonstrated that cisplatin promoted epithelial-mesenchymal transition (EMT), cell motility, and metastasis in vitro and in vivo. The bioinformatic analysis and molecular biology approaches also indicated that DCBLD2 is a key gene that mediates cispla-tin-induced metastasis. DCBLD2 stabilizes β-catenin by phosphorylating GSK3β and transporting accumulated β-catenin to the nucleus to promote the expression of EMT-related transcriptional factors (TFs), ultimately resulting in tumor metastasis. We also identified that cisplatin aggravated DCBLD2 expression by phosphorylating ERK and hence the AP-1-driven transcription of DCBLD2. Furthermore, DCBLD2-specific siRNAs encapsulated by nanocarriers prominently in-hibits cisplatin-induced metastasis in vivo. Therefore, DCBLD2 plays a key role in cispla-tin-induced metastasis in LUAD and is a potential target for preventing chemotherapy-induced metastasis in vivo.

2021-03-09 | GSE168498 | GEO

The neuroepithelial origin of ovarian carcinomas explained through anepithelial-mesenchymal-ectodermal transition enhanced by cisplatin

Project description:Acquired resistance to platinum-derived cytostatics poses major challenges in ovarian carcinoma therapy. In this work, we show a shift in the epithelial-mesenchymal transition (EMT) process towards an “ectodermal” conversion of ovarian carcinoma cells in response to cisplatin treatment, a progression we have termed epithelial-mesenchymal-ectodermal transition (EMET). EMET appears to occur via the classical EMT as judged by a) the downregulation of several epithelial markers and b) upregulation of Vimentin, accompanied by various embryonal transcription factors and, importantly, a plethora of neuronal markers, consistent with ectodermal differentiation. Moreover, we isolated cells from ovarian carcinoma cultures exhibiting a dual neural/stemness signature and multidrug resistance (MDR) phenotype. We also found that the epithelial cells differentiate from these neural/stem populations, indicating that the cell of origin in this tumor must in fact be a neural cell type with stemness features. Notably, some transcription factors like PAX6 and PAX9 were not localized in the nucleoplasm of these cells, hinting at altered nuclear permeability. In addition, the neuronal morphology was rapidly established when commercially available and primary ovarian carcinoma cells were cultured in the form of organoids. Importantly, we also identified a cell type in regular ovarian tissues, which possess similar neural/stemness features as observed in 2D or 3D cultures. The signature of this cell type is amplified in ovarian carcinoma tumors, suggesting a neuroepithelial origin of this tumor type. In conclusion, we propose that ovarian carcinomas harbor a small population of cells with an intrinsic neuronal/stemness/MDR phenotype, serving as the cradle from which ovarian carcinoma evolves.

2024-12-18 | GSE264296 | GEO

The neuroepithelial origin of ovarian carcinomas explained through anepithelial-mesenchymal-ectodermal transition enhanced by cisplatin

Project description:The neuroepithelial origin of ovarian carcinomas explained through anepithelial-mesenchymal-ectodermal transition enhanced by cisplatin

| PRJNA1101899 | ENA

Expression data from cultured human ovarian carcinoma cell lines with and without Cisplatin treatment

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

DCBLD2 Mediates Epithelial-Mesenchymal Transition-Induced Metastasis by Cisplatin in Lung Adenocarcinoma

Project description:DCBLD2 Mediates Epithelial-Mesenchymal Transition-Induced Metastasis by Cisplatin in Lung Adenocarcinoma

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Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion

Project description:Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion

| PRJNA611626 | ENA

Expression data from cultured human ovarian carcinoma cell lines with and without Cisplatin treatment

2014-07-29 | GSE47856 | GEO

Methylation profiling of cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines

Project description:Analysis of differences in DNA methylation in cisplatin-sensitive and cisplatin-resistant ovarian cancer cell lines.

2008-01-11 | E-TABM-210 | biostudies-arrayexpress