Overexpression of hsa_circ_0002874 promotes resistance of non-small cell lung cancer to paclitaxel by modulating miR-1273f/MDM2/p53 pathway

Aging (Albany NY). 2021 Feb 17;13(4):5986-6009. doi: 10.18632/aging.202521. Epub 2021 Feb 17.

Abstract

Background: This study aimed to investigate the aberrant expression of hsa_circ_0002874 in non-small cell lung cancer (NSCLC) and elucidate associated molecular mechanisms that influence apoptosis and induce paclitaxel (PTX) resistance.

Methods: Inhibitors were used to downregulate circRNA or miRNA expression. pCDNA plasmid transfection and mimics were used to upregulate circRNA or miRNA expression. Dual-luciferase reporter assays were conducted to evaluate interactions between miR1273f and MDM2. Xenograft tumor models were used to assess the effect of hsa_circ_0002874 and miR1273f on tumor growth. NSCLC tissues and matched non-cancerous tissues were also collected for correlation analysis.

Results: hsa_circ_0002874 acts as a sponge for miR1273f which targets MDM2/P53. The stability of the hsa_circ_0002874/miR1273f/MDM2/P53 pathway was verified by upregulating and downregulating the expression of hsa_circ_0002874 and miR1273f. hsa_circ_0002874 downregulation or miR1273f upregulation reversed the resistance of the A549/Taxol cells in xenograft models. The expression of hsa_circ_0002874 was high, and the level of MDM2 was low in NSCLC tissues. P53 was only weakly expressed in NSCLC tissues with high expression of MDM2.

Conclusions: hsa_circ_0002874 is strongly expressed in NSCLC tissues and maybe a potential marker for PTX resistance. hsa_circ_0002874 downregulation could regulate miR1273f/MDM2/P53 signaling pathway to reverse the PTX resistance of NSCLC and induce apoptosis in vitro and vivo.

Keywords: MDM2; P53; hsa_circ_0002874; miR1273f; paclitaxel-resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Aged
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Female
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Male
  • MicroRNAs / genetics
  • Middle Aged
  • Paclitaxel / pharmacology*
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • RNA, Circular
  • Signal Transduction*
  • Tumor Suppressor Protein p53

Substances

  • Antineoplastic Agents, Phytogenic
  • Biomarkers, Tumor
  • MIRN1273 microRNA, human
  • MicroRNAs
  • RNA, Circular
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • Paclitaxel