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Stiff substrates increase YAP-signaling-mediated matrix metalloproteinase-7 expression.

A Nukuda1, C Sasaki1, S Ishihara1,2

  • 1Transdisciplinary Life Science Course, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan.

Oncogenesis
|September 8, 2015
PubMed
Summary
This summary is machine-generated.

Stiff substrates promote colorectal cancer progression by increasing matrix metalloproteinase-7 (MMP-7) expression. A positive feedback loop involving YAP, EGFR, integrin-α2β1, and MRLC drives this effect, enhancing cancer cell viability.

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Area of Science:

  • Biomedical Engineering
  • Cancer Biology
  • Molecular Oncology

Background:

  • Abnormally stiff substrates are increasingly recognized as a factor in cancer progression.
  • The precise molecular mechanisms linking substrate stiffness to cancer progression remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which substrate stiffness influences colorectal cancer progression.
  • To investigate the role of matrix metalloproteinase-7 (MMP-7) and the yes-associated protein (YAP) signaling pathway in response to substrate stiffness.

Main Methods:

  • Cultured T84 human colorectal cancer cells on substrates of varying stiffness (plastic, collagen-I gel, polyacrylamide gels of 2, 67, and 126 kPa).
  • Assessed matrix metalloproteinase-7 (MMP-7) expression levels.
  • Utilized YAP knockdown, and inhibitors/knockdown of epidermal growth factor receptor (EGFR), myosin regulatory light chain (MRLC), integrin-α2, and integrin-β1.

Main Results:

  • Stiff substrates significantly enhanced MMP-7 expression, a marker of poor prognosis.
  • MMP-7 expression increased with substrate stiffness (126 kPa > 2 kPa).
  • YAP knockdown reduced MMP-7 expression; inhibition of EGFR, MRLC, integrin-α2, or integrin-β1 also downregulated MMP-7.
  • A positive feedback loop involving YAP, EGFR, integrin-α2β1, and MRLC was identified, which amplifies MMP-7 expression.

Conclusions:

  • Substrate stiffness enhances colorectal cancer cell viability.
  • Upregulation of MMP-7 expression via a YAP-driven positive feedback loop is a key mechanism mediating the pro-cancer effects of stiff substrates.