Interplay of transcription factors STAT3, STAT1 and AP-1 mediates activity of the matrix metallo-proteinase-1 promoter in colorectal carcinoma cells

Neoplasma. 2019 May 23;66(3):357-366. doi: 10.4149/neo_2018_180731N560. Epub 2018 Dec 12.


Signal Transducers (STATs) 1 and 3 and Activator Protein 1 (AP-1) are transcription factors involved in the development of malignancy in colorectal carcinoma (CRC). Matrix Metalloproteinase 1 (MMP-1) is a protease frequently dysregulated in de-differentiated and invasive cancer cells. Its expression is influenced by STAT and AP-1 transcription factors. We studied their contributions to transcriptional regulation of MMP-1 in colorectal carcinoma (CRC) cells. Both STAT3 and AP-1 contribute individual expression-inducing and additive effects and interact with the MMP-1 promoter. DNA binding of AP-1 protein c-Jun is stimulation-independent but modulated by STAT3 and a STAT recognition DNA element. Activated STAT3 showed a suppressive effect on AP-1-mediated MMP-1 mRNA upregulation as shown by STAT3 knockdown. Surprisingly, activated STAT1 overcame STAT3-dependent repression of AP-1-driven MMP-1 expression. Moreover, combined STAT3, STAT1 and AP-1 activities evoked maximal MMP-1 mRNA levels in a synergistic manner. Our results suggest a dominant role of AP-1 in transcriptional upregulation of MMP-1 in CRC cells which is modulated by joint functions of STAT3 and STAT1. The individual and combinatorial activity of these factors is of diagnostic and prognostic interest.

MeSH terms

  • Cell Line, Tumor
  • Colorectal Neoplasms* / enzymology
  • Colorectal Neoplasms* / genetics
  • Gene Expression Regulation, Neoplastic* / genetics
  • Humans
  • Matrix Metalloproteinase 1* / genetics
  • Matrix Metalloproteinase 1* / metabolism
  • Promoter Regions, Genetic* / genetics
  • STAT1 Transcription Factor* / metabolism
  • STAT3 Transcription Factor* / metabolism
  • Transcription Factor AP-1* / metabolism


  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Transcription Factor AP-1
  • Matrix Metalloproteinase 1