@Article{or.2023.030760,
AUTHOR = {MUNEEBA MALIK, MAMOONA MAQBOOL, TOOBA NISAR, TAZEEM AKHTER, JAVED AHMED UJAN, ALANOOD S. ALGARNI, FAKHRIA A. AL JOUFI, SULTAN SHAFI K. ALANAZI, MOHAMMAD HADI ALMOTARED, MOUNIR M. SALEM BEKHIT, MUHAMMAD JAMIL},
TITLE = {Deciphering key genes involved in cisplatin resistance in kidney renal clear cell carcinoma through a combined <i>in silico</i> and <i>in vitro</i> approach},
JOURNAL = {Oncology Research},
VOLUME = {31},
YEAR = {2023},
NUMBER = {6},
PAGES = {899--916},
URL = {http://www.techscience.com/or/v31n6/54210},
ISSN = {1555-3906},
ABSTRACT = {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 <i>in silico</i> and <i>in vitro</i> 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 (<i>p</i> < 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.},
DOI = {10.32604/or.2023.030760}
}