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Hypoxic conversion of SMAD7 function from an inhibitor into a promoter of cell invasion

Pekka T Heikkinen1, Marika Nummela, Terhi Jokilehto

  • 1Department of Otorhinolaryngology, Turku Centre for Biotechnology, Turku University and Abo Akademi University, School of Biological Sciences and Medicity Research Laboratories, Turku University Hospital, Turku, Finland.

Cancer Research
|June 17, 2010
PubMed

Insights

Hypoxia, or low oxygen, paradoxically activates Smad7, a protein usually inhibiting cancer invasion. This study reveals hypoxia converts Smad7 into an invasion promoter, explaining its elevated levels in many cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Smad7 normally inhibits transforming growth factor-beta (TGF-β) signaling and carcinoma cell invasion under normoxia.
  • Elevated Smad7 expression is observed in various cancers, often correlating with poorer prognosis.
  • Hypoxia is a common feature in solid tumors, promoting cancer cell invasion and progression.

Purpose of the Study:

  • To investigate the role of hypoxia in regulating Smad7 expression and function.
  • To determine if hypoxia alters Smad7's inhibitory effect on carcinoma cell invasion.
  • To elucidate the mechanism by which hypoxia influences Smad7 activity in cancer.

Main Methods:

  • Investigated Smad7 expression under hypoxia using hypoxia-inducible factor (HIF) and von Hippel-Lindau (VHL) protein dependency.
  • Assessed the impact of forced Smad7 expression on carcinoma cell invasion under normoxic and hypoxic conditions.
  • Utilized short interfering RNA (siRNA) to inhibit Smad7 expression and observed effects on hypoxia-induced invasion.
  • Correlated Smad7 expression with hypoxic gene expression in human carcinomas.

Main Results:

  • Hypoxia activates Smad7 expression in a HIF- and VHL-dependent manner.
  • Smad7's inhibitory effect on carcinoma cell invasion is abolished under hypoxic conditions.
  • Hypoxia releases the invasion-blocking effect of Smad7 in invasive cell lines.
  • Noninvasive keratinocytes gain invasiveness under combined hypoxia and TGF-β stimulation.
  • Inhibition of Smad7 attenuated hypoxia-driven invasion.
  • Increased Smad7 expression in human carcinomas correlates with hypoxic gene expression.

Conclusions:

  • Hypoxia can convert Smad7 from an invasion inhibitor into an invasion activator.
  • The study provides a potential explanation for the increased Smad7 expression observed in various cancers.
  • Understanding this hypoxia-mediated functional switch of Smad7 is crucial for cancer therapy development.

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