Mechanistic insights into epithelial-mesenchymal transition mediated cisplatin resistance in ovarian cancer
Abstract 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 OV90Cis...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-87388-8 |
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| author | Taha Umair Wani Hyun-Yi Kim Geum-Hwa Lee Young Je Lim Han-Jung Chae Ji-Ye Kim Hyonok Yoon |
| author_facet | Taha Umair Wani Hyun-Yi Kim Geum-Hwa Lee Young Je Lim Han-Jung Chae Ji-Ye Kim Hyonok Yoon |
| author_sort | Taha Umair Wani |
| collection | DOAJ |
| description | Abstract 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, we revealed through RNAseq analysis 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 Extracellular matrix (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. |
| format | Article |
| id | doaj-art-7de00dfe84f04c00a04027be467d2610 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Scientific Reports |
| spelling | doaj-art-7de00dfe84f04c00a04027be467d26102025-01-26T12:32:58ZengNature PortfolioScientific Reports2045-23222025-01-0115111310.1038/s41598-025-87388-8Mechanistic insights into epithelial-mesenchymal transition mediated cisplatin resistance in ovarian cancerTaha Umair Wani0Hyun-Yi Kim1Geum-Hwa Lee2Young Je Lim3Han-Jung Chae4Ji-Ye Kim5Hyonok Yoon6College of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National UniversityNGeneS IncNon-Clinical Evaluation Center, Biomedical Research Institute, Jeonbuk National University HospitalNon-Clinical Evaluation Center, Biomedical Research Institute, Jeonbuk National University HospitalSchool of Pharmacy and Institute of New Drug Development, Jeonbuk National UniversityDepartment of Pathology, Ilsan Paik Hospital, Inje University, College of MedicineCollege of Pharmacy, Research Institute of Pharmaceutical Sciences, Gyeongsang National UniversityAbstract 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, we revealed through RNAseq analysis 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 Extracellular matrix (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.https://doi.org/10.1038/s41598-025-87388-8Ovarian cancerCisplatin resistanceRNA sequencingEMTIntegrins |
| spellingShingle | Taha Umair Wani Hyun-Yi Kim Geum-Hwa Lee Young Je Lim Han-Jung Chae Ji-Ye Kim Hyonok Yoon Mechanistic insights into epithelial-mesenchymal transition mediated cisplatin resistance in ovarian cancer Scientific Reports Ovarian cancer Cisplatin resistance RNA sequencing EMT Integrins |
| title | Mechanistic insights into epithelial-mesenchymal transition mediated cisplatin resistance in ovarian cancer |
| title_full | Mechanistic insights into epithelial-mesenchymal transition mediated cisplatin resistance in ovarian cancer |
| title_fullStr | Mechanistic insights into epithelial-mesenchymal transition mediated cisplatin resistance in ovarian cancer |
| title_full_unstemmed | Mechanistic insights into epithelial-mesenchymal transition mediated cisplatin resistance in ovarian cancer |
| title_short | Mechanistic insights into epithelial-mesenchymal transition mediated cisplatin resistance in ovarian cancer |
| title_sort | mechanistic insights into epithelial mesenchymal transition mediated cisplatin resistance in ovarian cancer |
| topic | Ovarian cancer Cisplatin resistance RNA sequencing EMT Integrins |
| url | https://doi.org/10.1038/s41598-025-87388-8 |
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