Integrative microRNA and gene expression analysis identifies new epigenetically regulated microRNAs mediating taxane resistance in ovarian cancer

Abstract

Taxane is a family of front-line chemotherapeutic agents against ovarian cancer (OC). The therapeutic efficacy is frequently counteracted by the development of chemoresistance, leading to high rates of relapse in OC patients. The role(s) of microRNAs (miRNAs) in cancer chemoresistance had been supported by many evidences Epigenetic regulation by miRNAs has been reported to influence cancer development and response to therapeutics, however, their role in OC resistance to paclitaxel (PTX) is unclear. Here, we conducted miRNA profiling in the responsive and PTX-resistant OC cell lines before and after treatment with epigenetic modulators. We reveal 157 miRNAs to be downregulated in the PTX-resistant cells compared to parental controls. The expression of five miRNAs (miRNA-7-5p, -204-3p, -501-5p, -3652 and -4286) was restored after epigenetic modulation, which was further confirmed by qPCR. In silico analysis of the signaling pathways targeted by the selected miRNAs identified the PI3K-AKT pathway as the primary target. Subsequent cDNA array analysis confirmed multiple PI3K-AKT pathway members such as AKT2, PIK3R3, CDKN1A, CCND2 and FGF2 to be upregulated in PTX-resistant cells. STRING analysis showed the deregulated genes in PTX-resistant cells to be primarily involved in cell cycle progression and survival. Thus, high throughput miRNA and cDNA profiling coupled with pathway analysis and data mining provide evidence for epigenetically regulated miRNAs-induced modulation of signaling pathways in PTX resistant OC cells. It paves the way to more in-depth mechanistic studies and new therapeutic strategies to combat chemoresistance.

Cellular signaling modulated by miRNA-3652 in ovarian cancer: unveiling mechanistic pathways for future therapeutic strategies

“…By understanding the rationale behind these selections, researchers can prioritize which miRNAs to study, accelerating discoveries that might eventually translate into clinical benefits [ 5 , 66 ]. In the context of ovarian cancer, certain miRNAs have emerged as central players, either as oncogenes or tumor suppressors [ 28 , 61 ]. The rationale for selecting a specific miRNA for study within this malignancy often arises from a combination of factors [ 15 , 22 , 66 ]: Differential expression in ovarian tumors: many studies rely on high-throughput sequencing or microarray analyses to determine which miRNAs are upregulated or downregulated in tumor tissue compared to normal ovarian tissue.…”

“…However, the exact mechanisms and processes triggered by the dysregulation of miRNA-3652 in ovarian cancer patients remain unknown. Further research is required to unravel the specific consequences and underlying pathways associated with the dysregulation of miRNA-3652 in ovarian cancer patients [ 28 ]. In this study, the researchers investigated miRNA-3652’s system of likely target genes and its potential to cause cancer in OC cells.…”

“…Therefore the correlation between aberrant expression of miRNAs and OC-promoting genes regulated pathways can provide new insights into the clinical manifestation, diagnosis and treatment of OC [ 49 , 79 ]. Expression analysis has shown that the plasma and serum of ovarian cancer (OC) patients display downregulation of miRNA-3625 [ 28 , 40 ]. This downregulation is associated with dysregulation of tumor-suppressive genes and overexpression of tumor oncogenes.…”

“…This downregulation is associated with dysregulation of tumor-suppressive genes and overexpression of tumor oncogenes. Intriguingly, the OC patients that are resistant to front-line chemotherapeutic agents against OC [ 28 ] also show downregulation of mOC-resistant C-resistant cells exhibiting the epigenetic repairing of miRNA-3625 demonstrated to enhance the potency of therapeutic agents [ 14 ]. Overall, most of the reported studies on miRNAs were mainly focused on evaluating the abundance of miRNA along with speculations about their role in causing OC.…”

Down-regulation of microRNA-155 suppressed Candida albicans induced acute lung injury by activating SOCS1 and inhibiting inflammation response

“…Therefore, the development of new antifungal drugs is urgent. MicroRNA (miRNA) is an endogenous non-coding micro-RNA, and they could bind to the 3′ noncoding region of the target gene mRNA, induce mRNA degradation or hinder its translation (Hassan et al, 2021). MiRNAs are composed of 19-24 nucleotides, with a length change of 1-2 bases at the 3′ end.…”