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Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach

The low survival rate of Kidney renal clear cell carcinoma (KIRC) patients is largely attributed to cisplatin resistance. Rather than focusing solely on individual proteins, exploring protein-protein interactions could offer greater insight into drug resistance. To this end, a series of in silico an...

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Autores principales: MALIK, MUNEEBA, MAQBOOL, MAMOONA, NISAR, TOOBA, AKHTER, TAZEEM, UJAN, JAVED AHMED, ALGARNI, ALANOOD S., JOUFI, FAKHRIA A. AL, ALANAZI, SULTAN SHAFI K., ALMOTARED, MOHAMMAD HADI, BEKHIT, MOUNIR M. SALEM, JAMIL, MUHAMMAD
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Tech Science Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10513959/
https://www.ncbi.nlm.nih.gov/pubmed/37744271
http://dx.doi.org/10.32604/or.2023.030760
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author MALIK, MUNEEBA
MAQBOOL, MAMOONA
NISAR, TOOBA
AKHTER, TAZEEM
UJAN, JAVED AHMED
ALGARNI, ALANOOD S.
JOUFI, FAKHRIA A. AL
ALANAZI, SULTAN SHAFI K.
ALMOTARED, MOHAMMAD HADI
BEKHIT, MOUNIR M. SALEM
JAMIL, MUHAMMAD
author_facet MALIK, MUNEEBA
MAQBOOL, MAMOONA
NISAR, TOOBA
AKHTER, TAZEEM
UJAN, JAVED AHMED
ALGARNI, ALANOOD S.
JOUFI, FAKHRIA A. AL
ALANAZI, SULTAN SHAFI K.
ALMOTARED, MOHAMMAD HADI
BEKHIT, MOUNIR M. SALEM
JAMIL, MUHAMMAD
author_sort MALIK, MUNEEBA
collection PubMed
description The low survival rate of Kidney renal clear cell carcinoma (KIRC) patients is largely attributed to cisplatin resistance. Rather than focusing solely on individual proteins, exploring protein-protein interactions could offer greater insight into drug resistance. To this end, a series of in silico and in vitro experiments were conducted to identify hub genes in the intricate network of cisplatin resistance-related genes in KIRC chemotherapy. The genes involved in cisplatin resistance across KIRC were retrieved from the National Center for Biotechnology Information (NCBI) database using search terms as “Kidney renal clear cell carcinoma” and “Cisplatin resistance”. The genes retrieved were analyzed for hub gene identification using the STRING database and Cytoscape tool. Expression and promoter methylation profiling of the hub genes was done using UALCAN, GEPIA, OncoDB, and HPA databases. Mutational, survival, functional enrichment, immune cell infiltration, and drug prediction analyses of the hub genes were performed using the cBioPortal, GEPIA, GSEA, TIMER, and DrugBank databases. Lastly, expression and methylation levels of the hub genes were validated on two cisplatin-resistant RCC cell lines (786-O and A-498) and a normal renal tubular epithelial cell line (HK-2) using two high throughput techniques, including targeted bisulfite sequencing (bisulfite-seq) and RT-qPCR. A total of 124 genes were identified as being associated with cisplatin resistance in KIRC. Out of these genes, MCL1, IGF1R, CCND1, and PTEN were identified as hub genes and were found to have significant (p < 0.05) variations in their mRNA and protein expressions and effects on the overall survival (OS) of the KIRC patients. Moreover, an aberrant promoter methylation pattern was found to be associated with the dysregulation of the hub genes. In addition to this, hub genes were also linked with different cisplatin resistance-causing pathways. Thus, hub genes can be targeted with Alvocidib, Estradiol, Tretinoin, Capsaicin, Dronabinol, Metribolone, Calcitriol, Acetaminophen, Acitretin, Cyclosporine, Azacitidine, Genistein, and Resveratrol drugs. As the pathogenesis of KIRC is complex, targeting hub genes and associated pathways involved in cisplatin resistance could bring a milestone change in the drug discovery and management of drug resistance, which might uplift overall survival among KIRC patients.
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spelling pubmed-105139592023-09-23 Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach MALIK, MUNEEBA MAQBOOL, MAMOONA NISAR, TOOBA AKHTER, TAZEEM UJAN, JAVED AHMED ALGARNI, ALANOOD S. JOUFI, FAKHRIA A. AL ALANAZI, SULTAN SHAFI K. ALMOTARED, MOHAMMAD HADI BEKHIT, MOUNIR M. SALEM JAMIL, MUHAMMAD Oncol Res Article The low survival rate of Kidney renal clear cell carcinoma (KIRC) patients is largely attributed to cisplatin resistance. Rather than focusing solely on individual proteins, exploring protein-protein interactions could offer greater insight into drug resistance. To this end, a series of in silico and in vitro experiments were conducted to identify hub genes in the intricate network of cisplatin resistance-related genes in KIRC chemotherapy. The genes involved in cisplatin resistance across KIRC were retrieved from the National Center for Biotechnology Information (NCBI) database using search terms as “Kidney renal clear cell carcinoma” and “Cisplatin resistance”. The genes retrieved were analyzed for hub gene identification using the STRING database and Cytoscape tool. Expression and promoter methylation profiling of the hub genes was done using UALCAN, GEPIA, OncoDB, and HPA databases. Mutational, survival, functional enrichment, immune cell infiltration, and drug prediction analyses of the hub genes were performed using the cBioPortal, GEPIA, GSEA, TIMER, and DrugBank databases. Lastly, expression and methylation levels of the hub genes were validated on two cisplatin-resistant RCC cell lines (786-O and A-498) and a normal renal tubular epithelial cell line (HK-2) using two high throughput techniques, including targeted bisulfite sequencing (bisulfite-seq) and RT-qPCR. A total of 124 genes were identified as being associated with cisplatin resistance in KIRC. Out of these genes, MCL1, IGF1R, CCND1, and PTEN were identified as hub genes and were found to have significant (p < 0.05) variations in their mRNA and protein expressions and effects on the overall survival (OS) of the KIRC patients. Moreover, an aberrant promoter methylation pattern was found to be associated with the dysregulation of the hub genes. In addition to this, hub genes were also linked with different cisplatin resistance-causing pathways. Thus, hub genes can be targeted with Alvocidib, Estradiol, Tretinoin, Capsaicin, Dronabinol, Metribolone, Calcitriol, Acetaminophen, Acitretin, Cyclosporine, Azacitidine, Genistein, and Resveratrol drugs. As the pathogenesis of KIRC is complex, targeting hub genes and associated pathways involved in cisplatin resistance could bring a milestone change in the drug discovery and management of drug resistance, which might uplift overall survival among KIRC patients. Tech Science Press 2023-09-15 /pmc/articles/PMC10513959/ /pubmed/37744271 http://dx.doi.org/10.32604/or.2023.030760 Text en © 2023 Maqbool et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Article
MALIK, MUNEEBA
MAQBOOL, MAMOONA
NISAR, TOOBA
AKHTER, TAZEEM
UJAN, JAVED AHMED
ALGARNI, ALANOOD S.
JOUFI, FAKHRIA A. AL
ALANAZI, SULTAN SHAFI K.
ALMOTARED, MOHAMMAD HADI
BEKHIT, MOUNIR M. SALEM
JAMIL, MUHAMMAD
Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach
title Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach
title_full Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach
title_fullStr Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach
title_full_unstemmed Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach
title_short Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach
title_sort deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined in silico and in vitro approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10513959/
https://www.ncbi.nlm.nih.gov/pubmed/37744271
http://dx.doi.org/10.32604/or.2023.030760
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