Differential regulation of MMP7 in colon cancer cells resistant and sensitive to oxaliplatin-induced cell death

Cancer Biol Ther. 2011 Jan 1;11(1):4-13. doi: 10.4161/cbt.11.1.13672. Epub 2011 Jan 1.


Background: We have previously shown that metalloproteinase 7 (MMP7) expression is increased during the acquisition of resistance to oxaliplatin in colon cancer cells. Now we have analyzed the implication of β-catenin and EGFR pathways in the up-regulation of MMP7 in the oxaliplatin-resistant human colon cancer cell lines RHT29 and RHCT116 p53-/-, derived from the HT29 and HCT116 p53-/- cells, respectively.

Results: Oxaliplatin treatment increased EGFR expression and induced its activation in all the cell lines. However, β-catenin mRNA was only upregulated in the HT29 and RHT29 cells, with a marked increase in the nuclear/cytoplasmic β-catenin protein ratio in the oxaliplatin-resistant RHT29 cells. To determine the contribution of β-catenin and EGFR to the expression of MMP7 we performed siRNA experiments. β-catenin abrogation only prevented the induction of MMP7 by oxaliplatin in HT29 and RHT29 cells. Accordingly, viability of oxaliplatin-treated RHT29 cells under β-catenin silencing was decreased. On the other hand, EGFR siRNA induced contradictory effects, decreasing PEA3 and MMP7 expression in control and oxaliplatin-treated RHCT116 p53-/- cells but increasing basal- and oxaliplatin-induced PEA3 and MMP7 in the HT29 and RHT29 cells.

Conclusions: Oxaliplatin-induced MMP7 up-regulation is differentially achieved in colon cancer cell lines, as a result of EGFR and β-catenin cross-talk on MMP7 gene transcription. Taken together, our results point out the disparity of effects that β-catenin and EGFR blocking therapeutic strategies may exert on MMP7 expression depending on the cellular context and remark the importance of a better knowledge of MMP7 regulation to improve chemotherapy effectiveness in colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / enzymology*
  • Colonic Neoplasms / genetics
  • Drug Resistance, Neoplasm
  • Enzyme Activation / drug effects
  • ErbB Receptors / biosynthesis
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Matrix Metalloproteinase 7 / biosynthesis*
  • Matrix Metalloproteinase 7 / genetics
  • Organoplatinum Compounds / pharmacology*
  • Oxaliplatin
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Transcription Factors / metabolism
  • Transfection
  • Up-Regulation
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / biosynthesis
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Antineoplastic Agents
  • Organoplatinum Compounds
  • RNA, Small Interfering
  • Transcription Factors
  • beta Catenin
  • transcription factor PEA3
  • Oxaliplatin
  • ErbB Receptors
  • Matrix Metalloproteinase 7