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Characterization of a p53/miR-34a/CSF1R/STAT3 Feedback Loop in Colorectal Cancer

Xiaolong Shi1, Markus Kaller1, Matjaz Rokavec1

  • 1Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany.

Cellular and Molecular Gastroenterology and Hepatology
|April 19, 2020
PubMed
Abstract

Insights

The study reveals that CSF1R is a direct target of miR-34a, and their interaction impacts colorectal cancer (CRC) progression. Loss of this miR-34a/CSF1R axis promotes CRC metastasis and chemoresistance.

Area of Science:

  • Molecular oncology
  • Cancer epigenetics
  • Tumor microenvironment

Background:

  • The tumor suppressor p53 regulates miR-34a, which is frequently silenced in colorectal cancer (CRC).
  • Receptor tyrosine kinase CSF1R is identified as a direct target of miR-34a.
  • CSF1R acts as an effector in p53/miR-34a-mediated CRC suppression.

Purpose of the Study:

  • To investigate the role of CSF1R as a direct target of miR-34a in colorectal cancer.
  • To elucidate the functional consequences of the p53/miR-34a/CSF1R axis in CRC progression, metastasis, and chemoresistance.
  • To explore the therapeutic and prognostic implications of the miR-34a-CSF1R interaction in CRC management.

Main Methods:

  • Analysis of The Cancer Genome Atlas (TCGA) and other CRC cohorts for gene expression and patient survival.
  • Bioinformatic identification and experimental validation of microRNA and transcription factor targets.
  • Functional assays assessing epithelial-mesenchymal transition (EMT), invasion, migration, chemoresistance, and metastasis.
  • Analysis of protein expression and CpG methylation in human colon cancer samples.

Main Results:

  • Increased CSF1R, CSF1, and IL34 expression correlated with poor survival and mesenchymal subtype in primary CRCs.
  • CSF1R expression inversely correlated with miR-34a, due to direct miR-34a inhibition of CSF1R.
  • p53 induced miR-34a to repress CSF1R; SNAIL repressed miR-34a to induce CSF1R.
  • CSF1R activation promoted CRC cell EMT, migration, invasion, and metastasis via STAT3.
  • CpG methylation of miR-34a and subsequent CSF1R elevation mediated 5-FU resistance.
  • Elevated CSF1R at the tumor invasion front associated with miR-34a promoter methylation and distant metastasis.

Conclusions:

  • The reciprocal inhibition between miR-34a and CSF1R, and its disruption in tumors, holds potential for CRC therapeutic and prognostic strategies.
  • Targeting the miR-34a-CSF1R axis could offer novel approaches for colorectal cancer treatment.
  • Understanding the epigenetic regulation of miR-34a is crucial for managing CRC progression and chemoresistance.
Keywords:
5-FUChemoresistanceEMTMetastasisMicroRNAsTumor Progression

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