Circ_0003998 Regulates the Progression and Docetaxel Sensitivity of DTX-Resistant Non-Small Cell Lung Cancer Cells by the miR-136-5p/CORO1C Axis

Technol Cancer Res Treat. 2021 Jan-Dec:20:1533033821990040. doi: 10.1177/1533033821990040.

Abstract

Background: Drug resistance in cancer cells is a major challenge for anti-cancer therapy. Circular RNA (circRNA) circ_0003998 has been identified as an important regulator in the chemoresistance development of non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the molecular basis underlying the resistance control of circ_0003998 in NSCLC.

Methods: The levels of circ_0003998, miR-136-5p and coronin 1C (CORO1C) were gauged by the quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Cell viability, colony formation and apoptosis were evaluated by the Cell Counting Kit-8 (CCK-8), colony formation and flow cytometry assays, respectively. Targeted relationships among circ_0003998, miR-136-5p and CORO1C were confirmed by the dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Animal studies were performed to evaluate the function of circ_0003998 in vivo.

Results: Our data indicated that circ_0003998 expression was associated with NSCLC resistance to docetaxel (DTX). The knockdown of circ_0003998 promoted DTX sensitivity, suppressed cell colony formation, and enhanced cell apoptosis of A549/DTX and H1299/DTX cells in vitro. Moreover, circ_0003998 knockdown hampered tumor growth and enhanced DTX sensitivity in vivo. Mechanistically, circ_0003998 directly targeted miR-136-5p, and miR-136-5p was a molecular mediator of circ_0003998 function in vitro. Furthermore, CORO1C was a functionally important target of miR-136-5p in regulating DTX-resistant NSCLC cell colony formation, apoptosis and DTX sensitivity in vitro. Additionally, circ_0003998 modulated CORO1C expression by working as a miR-136-5p sponge.

Conclusion: Our present work identified that circ_0003998 regulated DTX-resistant NSCLC cell colony formation, apoptosis and DTX sensitivity at least partially by controlling CORO1C expression by sponging miR-136-5p, illuminating a rationale for developing circ_0003998 as a therapeutic target of chemoresistant NSCLC.

Keywords: CORO1C; NSCLC; chemoresistance; circ_0003998; miR-136-5p.

MeSH terms

  • 3' Untranslated Regions
  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Disease Models, Animal
  • Docetaxel / pharmacology
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Microfilament Proteins / genetics*
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Staging
  • RNA Interference
  • RNA, Circular*
  • Xenograft Model Antitumor Assays

Substances

  • 3' Untranslated Regions
  • MIRN136 microRNA, human
  • MicroRNAs
  • Microfilament Proteins
  • RNA, Circular
  • coronin proteins
  • Docetaxel