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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

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Oncology Research 2023年第6期31卷 899-916页

作者： MUNEEBA MALIK MAMOONA MAQBOOL TOOBA NISAR TAZEEM AKHTER JAVED AHMED UJAN ALANOOD SALGARNI FAKHRIA AAL JOUFI SULTAN SHAFI KALANAZI MOHAMMAD HADI ALMOTARED mounir msalem bekhit MUHAMMAD JAMIL Services Hospital LahorePakistan Sabzazar Medical Center LahorePakistan BHU Pourmiana AttockPakistan Public Health Department University of Health SciencesLahorePakistan Department of Zoology Shah Abdul Latif UniversityKhairpurPakistan Department of Animal Sciences University of FloridaGainesvilleUSA Pharmacology and Toxicology Department College of Pharmacy Umm Al-Qura UniversityMakkahSaudi Arabia Department of Pharmacology College of PharmacyJouf UniversityAljoufSaudi Arabia Regional Laboratory and Blood Bank(Total Laboratory Automation) RiyadhSaudi Arabia Health Affairs in Najran New Najran General HospitalNajranSaudi Arabia Department of Pharmaceutics College of PharmacyKing Saud UniversityRiyadhSaudi Arabia PARC Arid Zone Research Center Dera Ismail KhanPakistan

The low survival rate of Kidney renal clear cell carcinoma(KIRC)patients is largely attributed to cisplatin *** than focusing solely on individual proteins,exploring protein-protein interactions could offer greater insight into drug *** 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 *** 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 *** and promoter methylation profiling of the hub genes was done using UALCAN,GEPIA,OncoDB,and HPA ***,survival,functional enrichment,immune cell infiltration,and drug prediction analyses of the hub genes were performed using the cBioPortal,GEPIA,GSEA,TIMER,and DrugBank ***,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 *** 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 ***,an aberrant promoter methylation pattern was found to be associated with the dysregulation of the hub *** addition to this,hub genes were also linked with different cisplatin resistance-causing ***,hub genes can be targeted with Alvocidib,Estradiol,Tretinoin,Capsaicin,Dronabinol,Metribolone,Calcitriol

关键词： KIRC Cisplatin resistance Chemotherapy Overall survival

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Identifying and validating MMP family members(MMP2,MMP9,MMP12,and MMP16)as therapeutic targets and biomarkers in kidney renal clear cell carcinoma(KIRC)

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Oncology Research 2024年第4期32卷 737-752页

作者： KUNLUN LI DANDAN LI BARBOD HAFEZ mounir M.SALEM bekhit YOUSEF A.BIN JARDAN FARS KAED ALANAZI EHAB I.TAHA SAYED H.AUDA FAIQAH RAMZAN MUHAMMAD JAMIL The Second Affiliated Hospital of Harbin Medical University Harbin Medical UniversityHarbinChina Department of Pharmaceutical Engineering Jiangsu Ocean UniversityLianyungangChina Department of Biological Engineering University of SalfordSalfordUK Department of Pharmaceutics College of PharmacyKing Saud UniversityRiyadhSaudi Arabia Department of Animal and Poultry Production Faculty of Veterinary and Animal SciencesGomal UniversityDera Ismail KhanPakistan Department of Arid Zone Research PARC instituteDera Ismail KhanPakistan

Kidney Renal Clear Cell Carcinoma(KIRC)is a malignant tumor that carries a substantial risk of morbidity and *** MMP family assumes a crucial role in tumor invasion and *** study aimed to uncover the mechanistic relevance of the MMP gene family as a therapeutic target and diagnostic biomarker in Kidney Renal Clear Cell Carcinoma(KIRC)through a comprehensive approach encompassing both computational and molecular ***,Cytoscape,UALCAN,GEPIA,OncoDB,HPA,cBioPortal,GSEA,TIMER,ENCORI,DrugBank,targeted bisulfite sequencing(bisulfite-seq),conventional PCR,Sanger sequencing,and RT-qPCR based analyses were used in the present study to analyze MMP gene family members to accurately determine a few hub genes that can be utilized as both therapeutic targets and diagnostic biomarkers for *** performing STRING and Cytohubba analyses of the 24 MMP gene family members,MMP2(matrix metallopeptidase 2),MMP9(matrix metallopeptidase 9),MMP12(matrix metallopeptidase 12),and MMP16(matrix metallopeptidase 16)genes were denoted as hub genes having highest degree *** analyzing MMP2,MMP9,MMP12,and MMP16 via various TCGA databases and RT-qPCR technique across clinical samples and KIRC cell lines,interestingly,all these hub genes were found significantly overexpressed at mRNA and protein levels in KIRC samples relative to *** notable effect of the up-regulated MMP2,MMP9,MMP12,and MMP16 was also documented on the overall survival(OS)of the KIRC ***,targeted bisulfite-sequencing(bisulfite-seq)analysis revealed that promoter hypomethylation pattern was associated with up-regulation of hub genes(MMP2,MMP9,MMP12,and MMP16).In addition to this,hub genes were involved in various diverse oncogenic *** MMP gene family members(MMP2,MMP9,MMP12,and MMP16)may serve as therapeutic targets and prognostic biomarkers in KIRC.

关键词： KIRC MMP gene family Chemotherapy Overall survival

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