MicroRNA-155-5p promotes tumor progression and contributes to paclitaxel resistance via TP53INP1 in human breast cancer

MicroRNAs (miRNAs/miRs) are small, non-coding RNAs that are reported to serve numerous important regulatory functions; however, the role of miRNAs in regulating breast cancer cell biology remains poorly understood. Accumulating evidence has demonstrated that miRNAs orchestrate multiple cellular functions and serve crucial roles in cell differentiation and cancer development, either by acting as tumor suppressors or oncogenes. In particular, miR-155-5p expression levels have been found to be upregulated and serve as a prognostic marker in numerous types of solid cancer, including human breast cancer. More than half of patients with breast cancer benefit from treatment with adjuvant paclitaxel chemotherapy following the early postoperative period. Despite the initial response to intensive combination chemotherapy, the majority of most patients will eventually acquire resistance to the drug and succumb to their disease. Therefore, further investigations into the association between miRNAs and the mechanism of paclitaxel resistance are required. The results of the present study revealed a strong positive association between miR-155-5p expression levels and the paclitaxel resistance, as the expression levels of miR-155-5p were upregulated in resistant cells. MiR-155-5p was further validated to regulate paclitaxel resistance using gain- and loss-of-function experiments. TP53INP1 was identified as a direct target gene of miR-155-5p by combining the results from the prediction algorithm based on free energy minimization and reverse transcription-quantitative PCR (qRT-PCR) analysis. Also, miR-155-5p was suggested to be a key regulator of paclitaxel resistance in tumor cells, as it increased cell viability and motility, and promoted resistance to paclitaxel-induced apoptosis. The transfection with miR-155-5p inhibitors re-sensitized the paclitaxelresistant breast cancer cells, while the overexpression of miR-155-5p led to an increase in the resistance to paclitaxel. Furthermore, the overexpression of the target gene, TP53INP1, contributed to the re-sensitivity of drug-resistant cells to paclitaxel. The subsequent combination of the knockdown of miR-155-5p and the overexpression of TP53INP1 conferred paclitaxel sensitivity in resistant cells. These results may enhance the understanding of the molecular mechanisms underlying breast cancer progression and resistance to chemotherapy, and suggested that miR-155-5p or TP53INP1 may serve as novel therapeutic approaches to combat resistance to therapy, as well as the proliferation and evasion of apoptosis in breast cancer.

Automated summary

miRNAs play crucial roles in regulating breast cancer cell biology, with miR-155-5p being identified as a prognostic marker associated with paclitaxel resistance in breast cancer cells.