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Published on: May 8, 2012
Syndecan-1 and -4 differentially regulate oncogenic K-ras dependent cell invasion into collagen through α2β1 integrin
Karoliina Vuoriluoto1, Gunilla Högnäs, Pipsa Meller
1VTT Biotechnology, Turku, Finland.
Abstract:
Syndecans function as co-receptors for integrins on different matrixes. Recently, syndecan-1 has been shown to be important for α2β1 integrin-mediated adhesion to collagen in tumor cells by regulating cell adhesion and migration on two-dimensional collagen. However, the function of syndecans in supporting α2β1 integrin interactions with three-dimensional (3D) collagen is less well studied. Using loss-of-function and overexpression experiments we show that in 3D collagen syndecan-4 supports α2β1-mediated collagen matrix contraction. Cell invasion through type I collagen containing 3D extracellular matrix (ECM) is driven by α2β1 integrin and membrane type-1 matrix metalloproteinase (MT1-MMP). Here we show that mutational activation of K-ras correlates with increased expression of α2β1 integrin, MT1-MMP, syndecan-1, and syndecan-4. While K-ras-induced α2β1 integrin and MT1-MMP are positive regulators of invasion, silencing and overexpression of syndecans demonstrate that these proteins inhibit cell invasion into collagen. Taken together, these data demonstrate the existence of a complex interplay between integrin α2β1, MT1-MMP, and syndecans in the invasion of K-ras mutant cells in 3D collagen that may represent a mechanism by which tumor cells become more invasive and metastatic.
Insights
Syndecans, including syndecan-4, play a dual role in 3D collagen, supporting matrix contraction but inhibiting invasion. These findings reveal complex interactions influencing K-ras mutant cell metastasis.
Area of Science:
- Cell biology
- Extracellular matrix interactions
- Cancer research
Background:
- Syndecans act as co-receptors for integrins, influencing cell adhesion and migration.
- Syndecan-1 is known to mediate α2β1 integrin adhesion to 2D collagen in tumor cells.
- The role of syndecans in 3D collagen interactions with α2β1 integrin is less understood.
Purpose of the Study:
- To investigate the function of syndecans in α2β1 integrin-mediated interactions within 3D collagen.
- To elucidate the role of syndecans in K-ras mutant cell invasion through type I collagen.
Main Methods:
- Loss-of-function and overexpression experiments were employed.
- Analysis of α2β1 integrin, MT1-MMP, syndecan-1, and syndecan-4 expression in K-ras mutant cells.
- Assessment of cell invasion through 3D type I collagen matrices.
Main Results:
- Syndecan-4 supports α2β1 integrin-mediated collagen matrix contraction in 3D.
- K-ras activation correlates with increased expression of α2β1 integrin, MT1-MMP, syndecan-1, and syndecan-4.
- Despite promoting invasion via α2β1 integrin and MT1-MMP, syndecans (syndecan-1 and syndecan-4) were found to inhibit cell invasion into 3D collagen.
Conclusions:
- A complex interplay exists between α2β1 integrin, MT1-MMP, and syndecans in K-ras mutant cell invasion within 3D collagen.
- Syndecans exhibit a dual role, supporting matrix contraction while inhibiting invasion in 3D collagen.
- This intricate mechanism may contribute to tumor cell invasiveness and metastasis.
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