Comprehensive circular RNA profiling reveals the regulatory role of the circRNA-000911/miR-449a pathway in breast carcinogenesis

Int J Oncol. 2018 Mar;52(3):743-754. doi: 10.3892/ijo.2018.4265. Epub 2018 Feb 5.

Abstract

Circular RNAs (circRNAs) are key regulators in the development and progression of human cancers; however their roles in breast tumorigenesis are not yet well understood. Thus, the present study aimed to investigate the expression profiles and potential modulatory effects of circRNAs on breast carcinogenesis. A human circRNA microarray analysis was performed to screen for abnormally expressed circRNAs in breast cancer tissue and circRNA-000911 was identified as a circRNA which was significantly downregulated in breast cancer cells. Mechanistic investigations suggested that the enhanced expression of circRNA-000911 suppressed cell proliferation, migration and invasion, and promoted the apoptosis of breast cancer cells. By using a biotin-labeled circRNA-000911 probe to perform RNA precipitation in breast cancer cells, we identified miR‑449a as the circRNA‑000911-associated microRNA. Gain- and loss-of-function assays indicated that miR‑449a antagonized circRNA-000911 to regulate breast cancer progression. Subsequently, Notch1 was identified as the functional target of miR‑449a, and the overexpression of circRNA-000911 in breast cancer elevated Notch1 expression. Furthermore, Cignal Signal Transduction Reporter Array and western blot analysis identified nuclear factor-κB (NF-κB) signaling as a functional target of the circRNA-000911/miR‑449a pathway. On the whole, our findings indicate that circRNA-000911 plays an anti-oncogenic role in breast cancer and may thus serve as a promising therapeutic target for patients with breast cancer. Therefore, the overexpression of circRNA-000911 may provide a future direction which may aid in the development of a novel treatment strategy for breast cancer.

MeSH terms

  • Breast / pathology
  • Breast / surgery
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / surgery
  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Disease Progression
  • Down-Regulation
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Oligonucleotide Array Sequence Analysis / methods
  • RNA / genetics
  • RNA / metabolism*
  • RNA, Circular
  • Real-Time Polymerase Chain Reaction
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Signal Transduction / genetics
  • Up-Regulation

Substances

  • MIRN449 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • NOTCH1 protein, human
  • RNA, Circular
  • Receptor, Notch1
  • RNA