Screening miRNAs to Hinder the Tumorigenesis of Renal Clear Cell Carcinoma Associated with KDR Expression

Abstract

Introduction: This study delved to understand the role of Kinase Insert Domain Receptor (KDR) and its associated miRNAs in renal cell carcinoma through an extensive computational analysis. The potential of our findings to guide future research in this area is significant.

Methods: Our methods, which included the use of UALCAN and GEPIA2 databases, as well as miRDB, MirDIP, miRNet v2.0, miRTargetLink, MiEAA v2.1, TarBase v8.0, INTERNET, and miRTarBase, were instrumental in identifying the regulation of miRNA associated with KDR expression. The predicted miRNA was validated with the TCGA-KIRC patients' samples by implementing CancerMIRNome. The TargetScanHuman v8.0 was implemented to identify the associations between human miRNAs and KDR. A Patch Dock server analyzed the interactions between hsa-miR-200c-3p and KDR.

Results: The KDR expression rate was investigated in the Kidney Renal Cell Carcinoma (KIRC) samples, and adjacent normal tissues revealed that the expression rate was significantly higher than the normal samples, which was evident from the strong statistical significance (P = 1.63e^-12). Likely, the KDR expression rate was estimated as high at tumor grade 1 and gradually decreased till the metastasis grade, reducing the survival rate of the KIRC patients. To identify these signals early, we predicted a miRNA that could alter the expression of KDR. Furthermore, we uncovered the potential associations between miR-200c-3p expressions by regulating KDR towards the progression of KIRC.

Discussion: Upon examining the outcome, it became evident that miR-200c-3p was significantly downregulated in KIRC compared to the normal samples. Moreover, the negative correlation was obtained for hsa-miR-200c-3p (R = - 0.276) along with the KDR expression describing that the increased rate of hsamiR- 200c-3p might reduce the KDR expression rate, which may suppress the KIRC initiation or progression.

Conclusion: The in-silico analysis indicated that the significant increase in KDR expression during the initiation of KIRC could serve as an early diagnostic marker. Moreover, KDR could be utilized to identify advancements in KIRC stages. Additionally, hsa-miR-200c-3p was identified as a potential regulator capable of downregulating and upregulating KDR expression among the 24 miRNAs screened. This finding holds promise for future research endeavors. Concurrent administration of the FDA-approved 5- fluorouracil with KIRC drugs, such as sorafenib, zidovudine, and everolimus, may have the potential to enhance the therapeutic efficacy in downregulating hsa-miR-200c-3p. However, further in vitro studies are imperative to validate these findings and gain a comprehensive understanding of the intricate regulatory interplay involving hsa-miR-200c-3p, KDR, 5-fluorouracil, and other FDA-approved drugs for the treatment of KIRC. This will facilitate the identification of KIRC stage progression and its underlying preventative mechanisms.

Keywords: KDR; computational kidney; miR-200c-3p.; miRNA; renal cell carcinoma; tumor grade potential regulator.