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Molecular Analysis of Endothelial-mesenchymal Transition Induced by Transforming Growth Factor-β Signaling
07:49

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Published on: August 3, 2018

Epidermal growth factor receptor regulates MT1-MMP and MMP-2 synthesis in SiHa cells via both PI3-K/AKT and MAPK/ERK

Zongfeng Zhang1, Tiefang Song, Yinglan Jin

  • 1Department of Obstetrics and Gynecology, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Harbin, China.

International Journal of Gynecological Cancer : Official Journal of the International Gynecological Cancer Society
|October 13, 2009
PubMed

Insights

Epidermal growth factor (EGF) regulates matrix metalloproteinase 2 (MMP-2) and membrane type 1 matrix metalloproteinase (MT1-MMP) in cervical cancer cells. EGF upregulates MT1-MMP and downregulates MMP-2 via the MAPK/ERK pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Matrix metalloproteinases (MMPs), including MMP-2 and MT1-MMP, are crucial in tumor progression, invasion, metastasis, and angiogenesis.
  • MT1-MMP is a key activator of MMP-2, highlighting their interconnected roles in cancer.
  • Understanding the regulation of these MMPs by growth factors is vital for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the signal transduction pathways by which epidermal growth factor (EGF) regulates MMP-2 and MT1-MMP expression and activity in SiHa cervical cancer cells.
  • To elucidate the specific roles of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3-K)/AKT pathways in mediating EGF's effects on MMP-2 and MT1-MMP.

Main Methods:

  • SiHa cervical cancer cells were treated with EGF and specific pathway inhibitors (PD98059, U0126 for MAPK/ERK; LY294002, wortmannin for PI3-K).
  • Expression levels of MMP-2 and MT1-MMP were analyzed at both mRNA and protein levels using quantitative PCR and Western blotting.
  • MMP-2 activity in the culture media was assessed.

Main Results:

  • EGF treatment significantly induced MT1-MMP expression while inhibiting MMP-2 expression at both mRNA and protein levels in SiHa cells.
  • MAPK/ERK pathway inhibitors (PD98059, U0126) blocked EGF-induced MT1-MMP expression and enhanced MMP-2 expression.
  • PI3-K pathway inhibitors (LY294002, wortmannin) further suppressed MMP-2 expression but did not affect MT1-MMP induction by EGF.
  • EGF treatment led to elevated MMP-2 activity in the cell culture supernatant.

Conclusions:

  • EGF receptor signaling upregulates MT1-MMP and downregulates MMP-2 via the MAPK/ERK pathway in SiHa cells.
  • The PI3-K/AKT pathway plays a secondary role in positively regulating MMP-2 expression under EGF stimulation.
  • These findings reveal complex, pathway-specific regulation of MMP-2 and MT1-MMP by EGF, offering potential therapeutic targets in cervical cancer.

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