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Integrated mRNA and miRNA Transcriptomic Analyses Reveals Divergent Mechanisms of Sunitinib Resistance in Clear Cell Renal Cell Carcinoma (ccRCC).

ABSTRACT: The anti-angiogenic therapy sunitinib remains the standard first-line treatment for meta static clear cell renal cell carcinoma (ccRCC). However, acquired resistance develops in nearly all responsive patients and represents a major source of treatment failure. We used an integrated miRNA and mRNA transcriptomic approach to identify miRNA:target gene interactions involved in sunitinib resistance. Through the generation of stably resistant clones in three ccRCC cell lines (786-O, A498 and Caki-1), we identified non-overlapping miRNA:target gene networks, suggesting divergent mechanisms of sunitinib resistance. Surprisingly, even though the genes involved in these networks were different, they shared targeting by multiple members of the miR-17~92 cluster. In 786-O cells, targeted genes were related to hypoxia/angiogenic pathways, whereas, in Caki-1 cells, they were related to inflammatory/proliferation pathways. The immunotherapy target PD-L1 was consistently up-regulated in resistant cells, and we demonstrated that the silencing of this gene resulted in an increase in sensitivity to sunitinib treatment only in 786-O-resistant cells, suggesting that some ccRCC patients might benefit from combination therapy with PD-L1 checkpoint inhibitors. In summary, we demonstrate that, although there are clearly divergent mechanisms of sunitinib resistance in ccRCC subtypes, the commonality of miRNAs in multiple pathways could be targeted to overcome sunitinib resistance.

SUBMITTER: Armesto M

PROVIDER: S-EPMC8430814 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionEndometriosis, a benign inflammatory disease whereby endometrial-like tissue grows outside the uterus, is a risk factor for endometriosis-associated ovarian cancers. In particular, ovarian endometriomas, cystic lesions of deeply invasive endometriosis, are considered the precursor lesion for ovarian clear-cell carcinoma (OCCC).MethodsTo explore this transcriptomic landscape, OCCC from women with pathology-proven concurrent endometriosis (n = 4) were compared to benign endometriomas (n = 4) by bulk RNA and small-RNA sequencing.ResultsAnalysis of protein-coding genes identified 2449 upregulated and 3131 downregulated protein-coding genes (DESeq2, P< 0.05, log2 fold-change > |1|) in OCCC with concurrent endometriosis compared to endometriomas. Gene set enrichment analysis showed upregulation of pathways involved in cell cycle regulation and DNA replication and downregulation of pathways involved in cytokine receptor signaling and matrisome. Comparison of pathway activation scores between the clinical samples and publicly-available datasets for OCCC cell lines revealed significant molecular similarities between OCCC with concurrent endometriosis and OVTOKO, OVISE, RMG1, OVMANA, TOV21G, IGROV1, and JHOC5 cell lines. Analysis of miRNAs revealed 64 upregulated and 61 downregulated mature miRNA molecules (DESeq2, P< 0.05, log2 fold-change > |1|). MiR-10a-5p represented over 21% of the miRNA molecules in OCCC with endometriosis and was significantly upregulated (NGS: log2fold change = 4.37, P = 2.43e-18; QPCR: 8.1-fold change, P< 0.05). Correlation between miR-10a expression level in OCCC cell lines and IC50 (50% inhibitory concentration) of carboplatin in vitro revealed a positive correlation (R2 = 0.93). MiR-10a overexpression in vitro resulted in a significant decrease in proliferation (n = 6; P< 0.05) compared to transfection with a non-targeting control miRNA. Similarly, the cell-cycle analysis revealed a significant shift in cells from S and G2 to G1 (n = 6; P< 0.0001). Bioinformatic analysis predicted that miR-10a-5p target genes that were downregulated in OCCC with endometriosis were involved in receptor signaling pathways, proliferation, and cell cycle progression. MiR-10a overexpression in vitro was correlated with decreased expression of predicted miR-10a target genes critical for proliferation, cell-cycle regulation, and cell survival including [SERPINE1 (3-fold downregulated; P< 0.05), CDK6 (2.4-fold downregulated; P< 0.05), and RAP2A (2-3-fold downregulated; P< 0.05)].DiscussionThese studies in OCCC suggest that miR-10a-5p is an impactful, potentially oncogenic molecule, which warrants further studies.

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Integrated mRNA and miRNA Transcriptomic Analyses Reveals Divergent Mechanisms of Sunitinib Resistance in Clear Cell Renal Cell Carcinoma (ccRCC).

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