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

Pathol Res Pract. 2021 Apr:220:153405. doi: 10.1016/j.prp.2021.153405. Epub 2021 Mar 5.

Abstract

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 paclitaxel-resistant 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.

Keywords: Breast cancer; Invasion; Migration; Paclitaxel resistance; TP53INP1; miR-155-5p.

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Databases, Genetic
  • Drug Resistance, Neoplasm* / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • MCF-7 Cells
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Middle Aged
  • Neoplasm Invasiveness
  • Paclitaxel / pharmacology*

Substances

  • Antineoplastic Agents, Phytogenic
  • Carrier Proteins
  • Heat-Shock Proteins
  • MIRN155 microRNA, human
  • MicroRNAs
  • TP53INP1 protein, human
  • Paclitaxel