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The miR-124-p63 feedback loop modulates colorectal cancer growth

Oncotarget. 2017 Apr 25;8(17):29101-29115. doi: 10.18632/oncotarget.16248.

Abstract

Among the diverse co-regulatory relationships between transcription factors (TFs) and microRNAs (miRNAs), feedback loops have received the most extensive research attention. The co-regulation of TFs and miRNAs plays an important role in colorectal cancer (CRC) growth. Here, we show that miR-124 can regulate two isoforms of p63, TAp63 and ΔNp63, via iASPP, while p63 modulates signal transducers and activators of transcription 1 (STAT1) expression by targeting miR-155. Moreover, STAT1 acts as a regulator of CRC growth by targeting miR-124. Taken together, these results reveal a feedback loop between miRNAs and TFs. This feedback loop comprises miR-124, iASPP, STAT1, miR-155, TAp63 and ΔNp63, which are essential for CRC growth. Moreover, this feedback loop is perturbed in human colon carcinomas, which suggests that the manipulation of this microRNA-TF feedback loop has therapeutic potential for CRC.

Keywords: cell growth; colorectal cancer; feedback loop; miR-124; p63.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromatin Immunoprecipitation
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • Feedback, Physiological*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Protein Isoforms / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Intracellular Signaling Peptides and Proteins
  • MIRN124 microRNA, human
  • MIRN155 microRNA, human
  • MicroRNAs
  • PPP1R13L protein, human
  • Protein Isoforms
  • RNA, Small Interfering
  • Repressor Proteins
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins