Deciphering the Role of Putative Novel miRNAs Encoded From the Newly Found Genomic Regions of T2T-CHM13 in the Progression of Collecting Duct Renal Cell Carcinoma.

BACKGROUND

Collecting duct renal cell carcinoma (cdRCC) is a rare and aggressive renal cancer subtype. The molecular mechanisms underlying cdRCC remain poorly understood, which presents a significant challenge for the development of effective treatment strategies. Advances in genome sequencing, particularly the discovery of new genomic regions in the T2T-CHM13 reference genome, have provided an opportunity to expand our understanding of this disease.

AIMS

Our study specifically aims to investigate the role of miRNAs encoded by these regions, proposing them as potential epigenetic regulators in the pathogenesis of cdRCC.

METHODS

We used bioinformatic pipelines and small RNA-seq data analysis to predict novel miRNAs from the newly discovered genomic regions of T2T-CHM13. RNA-seq analysis of cdRCC tumors was performed to identify differentially expressed genes, and target prediction tools were used to find miRNA-mRNA interactions. Functional enrichment analyses were conducted to characterize the biological pathways affected.

RESULTS AND DISCUSSION

Using computational approaches, we predicted 156 novel miRNAs from T2T-CHM13's newly resolved sequences. RNA-seq and miRNA-mRNA interaction analyses identified 345 downregulated genes targeted by novel miRNAs and 395 downregulated genes targeted by known miRNAs. A comprehensive functional enrichment analysis of these perturbed genes revealed distinctive pathways, including cGMP-PKG signaling, calcium signaling, adipocytokine signaling, PPAR signaling, and apelin signaling, all of which are implicated in tumorigenesis. Furthermore, Gene Ontology analysis linked miRNA-targeted genes to disrupted cell-cell junctions and adhesion, providing a mechanistic explanation for aggressive invasion and metastasis in cdRCC. Additionally, a significant number of the target genes involved in metabolic and ion transport pathways were perturbed, explaining metabolic alterations in the cancer cells. We also identified 15 tumor suppressor genes downregulated by novel miRNAs, 6 of which were uniquely targeted, highlighting the potential of these miRNAs as cdRCC-specific biomarkers.

CONCLUSION

In conclusion, our study offers valuable insights into cdRCC biology from an epigenetic perspective, laying the groundwork for future research aimed at developing targeted therapies.