Upregulated METTL3 promotes metastasis of colorectal Cancer via miR-1246/SPRED2/MAPK signaling pathway

J Exp Clin Cancer Res. 2019 Sep 6;38(1):393. doi: 10.1186/s13046-019-1408-4.


Background: m6A modification has been proved to play an important role in many biological processes. METTL3 as the main methyltransferase for methylation process has been found to be upregulated in many cancers, including CRC. Here, we investigate m6A modification and the underlying mechanism of METTL3 in the development of CRC.

Methods: The expression of METTL3 was detected in large clinical patient samples. To evaluate the function of METTL3 in vitro and in vivo, colony formation, CCK-8, cell migration and invasion assays were performed. To find out the downstream target of METTL3, GEO dataset was re-mined. We analyzed expression and metastasis-related miRNA by Pearson correlation, and miR-1246 was selected. Here, to identify the downstream target of miR-1246, Targetscan and miRWalk were used. RIP and luciferase reporter assay further confirmed SPRED2 as the direct target of miR-1246.

Results: We found that upregulated METTL3 is responsible for abnormal m6A modification in CRC and correlates positively with tumor metastasis. The gain- and loss-of-function indicates that METTL3 promotes cell migration and invasion in vitro and in vivo. Additionally, we confirmed that METTL3 can methylate pri-miR-1246, which further promotes the maturation of pri-miR-1246. By using bioinformatics tools, anti-oncogene SPRED2 was identified as the downstream target of miR-1246, wherein downregulated SPRED2 further reverses the inhibition of the MAPK pathway.

Conclusions: The present study demonstrates that the METTL3/miR-1246/SPRED2 axis plays an important role in tumor metastasis and provides a new m6A modification pattern in CRC development.

Keywords: CRC; METTL3; Tumor invasion; m6A modification; miR-1246.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter
  • Humans
  • Male
  • Methyltransferases / genetics*
  • Methyltransferases / metabolism
  • Mice
  • MicroRNAs / genetics*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Models, Biological
  • RNA Interference
  • Repressor Proteins / genetics*
  • Signal Transduction*


  • MIRN1246 microRNA, human
  • MicroRNAs
  • Repressor Proteins
  • SPRED2 protein, human
  • Methyltransferases
  • METTL3 protein, human
  • Mitogen-Activated Protein Kinases