IRF-1 mediated long non-coding RNA PVT1-214 promotes oxaliplatin resistance of colorectal cancer via miR-128 inhibition

J BUON. 2020 Sep-Oct;25(5):2205-2214.

Abstract

Purpose: Long non-coding RNA (lncRNA) plasmacytoma variant translocation 1-214 transcript (PVT1-214) is a notable lncRNA involved in gastric cancer and colorectal cancer (CRC) so far. Nowadays, the biological function of PVT1-214 on the response of CRC to chemotherapy is still unclear. We aimed to explore the molecular mechanism of PVT1-214 and its regulatory mechanism in advanced CRC.

Methods: The levels of PVT1-214, microRNA (miR)-128, and interferon regulatory factor-1 (IRF-1) in CRC tissues and cell lines were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Log-rank test was applied to evaluate the role of high PVT1-214 levels in shortening the overall survival of CRC patients. Chi-square test was to assess the relation between PVT1-214 expression and clinicopathological features of CRC patients. CCK8 assays tested the cell proliferation of oxaliplatin-resistant CRC cells (HCT116/Oxa and SW480/Oxa) with PVT1-214 knockdown. The underlying regulatory mechanism between PVT1-214 and miR-128 was predicted by bioinformatics and verified by RNA transfection, qRT-PCR and western blotting. Chromatin immunoprecipitation (ChIP) assay was done to examine the relationship between or IRF-1 and the PVT1-214 gene.

Results: High levels of PVT1-214 expression were more likely to be present in patients with late-stage (IV), chemotherapy resistance, and inferior overall survival. PVT1-214 was aberrantly elevated in oxaliplatin-resistant CRC tissues and cell lines (HCT116/Oxa and SW480/Oxa). PVT1-214 knockdown reduced cell proliferation, migration and invasion of oxaliplatin-resistant CRC cells in vitro. Moreover, IRF-1 was found to be a negative transcription regulator of PVT1-214 and decreased PVT1-214 levels in oxaliplatin-resistant CRC cells. Besides, PVT1-214 repressed miR-128 function by binding to the complementary sites of miR-128.

Conclusions: IRF-1/PVT1-214 may markedly boost the oxaliplatin-resistance of CRC, resulting in the late TNM stage and poor survival. These findings suggest that the IRF-1/PVT1-214 axis may be a helpful target for intervention in CRC.

MeSH terms

  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Female
  • Humans
  • Interferon Regulatory Factor-1 / metabolism*
  • Male
  • MicroRNAs / metabolism*
  • Middle Aged
  • Oxaliplatin / pharmacology
  • Oxaliplatin / therapeutic use*
  • RNA, Long Noncoding / genetics*
  • Transfection

Substances

  • Interferon Regulatory Factor-1
  • MIRN128 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • Oxaliplatin