The Plasma microRNA miR-1914* and -1915 Suppresses Chemoresistant in Colorectal Cancer Patients by Down-regulating NFIX

Curr Mol Med. 2016;16(1):70-82. doi: 10.2174/1566524016666151222144656.

Abstract

Objective: We investigated mechanisms of colorectal cancer (CRC) chemoresistance to first-line chemotherapy (capecitabine plus oxaliplatin (XELOX)) and identified two putative chemoresistant microRNAs, miR-1914* and -1915, that are downregulated in plasma samples from patients with chemoresistant CRC.

Methods: A number of plasma samples from CRC patients were analyzed for the levels of miR-1914* and - 1915. Effects of stable and transient expression of 2 microRNAs in human chemoresistant CRC cell lines were analyzed. Tumor formation and chemoresistance in HCT116/5-Fu/OXA that did or did not express 2 microRNAs were analyzed in mice. Nuclear factor I/X (NFIX) was predicted to target the gene of 2 miRNAs and verified in vivo and in vitro.

Results: Plasma levels of miR-1914* and -1915 in chemoresistant CRC patients were different than levels in responders, and associated with clinical response. Overexpression of miR-1914* and -1915 in chemoresistant CRC cells reduced resistance to 5-FU and Oxaliplatin in vitro. The microRNAs suppressed chemoresistance in CRC tumors in mice by affecting cell growth, invasion, apoptosis and tumor suppressor function. miR-1914* and -1915 interacted with the 3'-untranslated region of NFIX and reduced NFIX its level in chemoresistant CRC cells. Overexpression of NFIX did not inhibit chemoresistant CRC cell motility and chemoresistant proteins when miR-1914* and -1915 were transfected.

Conclusion: Plasma miR-1914* and -1915 interact with NFIX RNA and reduce its level in chemoresistant CRC cells to first-line chemotherapy. Up-regulation of miR-1914* and -1915 decreased the chemoresistance abilities of chemoresistant CRC cells. The plasma miR-1914* and -1915 may play a role in colorectal cancer therapy and diagnosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Capecitabine / therapeutic use
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / blood*
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Down-Regulation / drug effects
  • Down-Regulation / genetics*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Fluorouracil / analogs & derivatives
  • Fluorouracil / therapeutic use
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Genes, Tumor Suppressor / physiology*
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / blood*
  • Middle Aged
  • NFI Transcription Factors / genetics*
  • Organoplatinum Compounds / therapeutic use
  • Oxaliplatin
  • Oxaloacetates

Substances

  • MIRN1915 microRNA, human
  • MicroRNAs
  • NFI Transcription Factors
  • NFIX protein, human
  • Organoplatinum Compounds
  • Oxaloacetates
  • Oxaliplatin
  • Deoxycytidine
  • Capecitabine
  • Fluorouracil

Supplementary concepts

  • XELOX