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Cleavage of E-Cadherin by Matrix Metalloproteinase-7 Promotes Cellular Proliferation in Nontransformed Cell Lines via Activation of RhoA.

Lynch CC, Vargo-Gogola T, Matrisian LM, Fingleton B - J Oncol (2010)

Bottom Line: Previously, we demonstrated that MMP-7, a protease implicated in mammary and intestinal tumor growth, can process the adherens junction component E-cadherin.This observation leads us to test whether MMP-7 processing of E-cadherin could directly impact cell proliferation in nontransformed epithelial cell lines (MDCK and C57MG).Our goal was to investigate the possibility that MMP-7 produced by cancer cells may have effects on adjacent normal epithelium.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, 734 PRB 2220 Pierce Ave, Nashville, TN 37232, USA.

ABSTRACT
Perturbations in cell-cell contact machinery occur frequently in epithelial cancers and result in increased cancer cell migration and invasion. Previously, we demonstrated that MMP-7, a protease implicated in mammary and intestinal tumor growth, can process the adherens junction component E-cadherin. This observation leads us to test whether MMP-7 processing of E-cadherin could directly impact cell proliferation in nontransformed epithelial cell lines (MDCK and C57MG). Our goal was to investigate the possibility that MMP-7 produced by cancer cells may have effects on adjacent normal epithelium. Here, we show that MMP-7 processing of E-cadherin mediates, (1) loss of cell-cell contact, (2) increased cell migration, (3) a loss of epithelial cell polarization and (4) increased cell proliferation via RhoA activation. These data demonstrate that MMP-7 promotes epithelial cell proliferation via the processing of E-cadherin and provide insights into the molecular mechanisms that govern epithelial cell growth.

No MeSH data available.


Related in: MedlinePlus

MMP-7 promotes E-cadherin processing. (a) Detection of the ectodomain of E-cadherin (80 kDa, open arrow head) in the conditioned media of MDCK cells in the presence (+) or absence (−) of exogenous MMP-7 (100 ng/mL).  (b) Analysis of E-cadherin processing in the empty vector control (L2 and L4) and MMP-7 (M14 and M37) expressing cell lines. Open arrow head indicates the ectodomain of E-cadherin (80 kDa) in conditioned media, while arrow and arrow head indicate full length E-cadherin (120 kDa) and intracellular fragment of E-cadherin (40 kDa), respectively, in C57MG cell line lysates.
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fig4: MMP-7 promotes E-cadherin processing. (a) Detection of the ectodomain of E-cadherin (80 kDa, open arrow head) in the conditioned media of MDCK cells in the presence (+) or absence (−) of exogenous MMP-7 (100 ng/mL). (b) Analysis of E-cadherin processing in the empty vector control (L2 and L4) and MMP-7 (M14 and M37) expressing cell lines. Open arrow head indicates the ectodomain of E-cadherin (80 kDa) in conditioned media, while arrow and arrow head indicate full length E-cadherin (120 kDa) and intracellular fragment of E-cadherin (40 kDa), respectively, in C57MG cell line lysates.

Mentions: The adherens junction in epithelial cells contains numerous complexes that allow the formation of tight cell-cell contacts. Previously, we identified that MMP-7 was capable of processing E-cadherin in transformed cells, at the juxtamembrane region, resulting in the generation of 80 kDa ectodomain and 40 kDa intracellular domain fragments [8]. Therefore, we next tested whether MMP-7 was responsible for E-cadherin processing in the MDCK and C57MG cells. We observed by immunoprecipitation that the addition of exogenous MMP-7 to confluent MDCK cells resulted in the shedding of the E-cadherin ectodomain into the conditioned media (Figure 4(a)). In confluent MMP-7 expressing C57MG cell lines, we also identified significantly higher levels of the E-cadherin ectodomain in conditioned media compared to the empty vector control cell lines (Figure 4(b)). In agreement with enhanced shedding of the ectodomain, we identified higher levels of the 40 kDa intracellular domain in the MMP-7 expressing cell lines compared to the control (Figure 4(b)). These data demonstrate that MMP-7 mediates E-cadherin processing in nontransformed epithelial cell lines.


Cleavage of E-Cadherin by Matrix Metalloproteinase-7 Promotes Cellular Proliferation in Nontransformed Cell Lines via Activation of RhoA.

Lynch CC, Vargo-Gogola T, Matrisian LM, Fingleton B - J Oncol (2010)

MMP-7 promotes E-cadherin processing. (a) Detection of the ectodomain of E-cadherin (80 kDa, open arrow head) in the conditioned media of MDCK cells in the presence (+) or absence (−) of exogenous MMP-7 (100 ng/mL).  (b) Analysis of E-cadherin processing in the empty vector control (L2 and L4) and MMP-7 (M14 and M37) expressing cell lines. Open arrow head indicates the ectodomain of E-cadherin (80 kDa) in conditioned media, while arrow and arrow head indicate full length E-cadherin (120 kDa) and intracellular fragment of E-cadherin (40 kDa), respectively, in C57MG cell line lysates.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig4: MMP-7 promotes E-cadherin processing. (a) Detection of the ectodomain of E-cadherin (80 kDa, open arrow head) in the conditioned media of MDCK cells in the presence (+) or absence (−) of exogenous MMP-7 (100 ng/mL). (b) Analysis of E-cadherin processing in the empty vector control (L2 and L4) and MMP-7 (M14 and M37) expressing cell lines. Open arrow head indicates the ectodomain of E-cadherin (80 kDa) in conditioned media, while arrow and arrow head indicate full length E-cadherin (120 kDa) and intracellular fragment of E-cadherin (40 kDa), respectively, in C57MG cell line lysates.
Mentions: The adherens junction in epithelial cells contains numerous complexes that allow the formation of tight cell-cell contacts. Previously, we identified that MMP-7 was capable of processing E-cadherin in transformed cells, at the juxtamembrane region, resulting in the generation of 80 kDa ectodomain and 40 kDa intracellular domain fragments [8]. Therefore, we next tested whether MMP-7 was responsible for E-cadherin processing in the MDCK and C57MG cells. We observed by immunoprecipitation that the addition of exogenous MMP-7 to confluent MDCK cells resulted in the shedding of the E-cadherin ectodomain into the conditioned media (Figure 4(a)). In confluent MMP-7 expressing C57MG cell lines, we also identified significantly higher levels of the E-cadherin ectodomain in conditioned media compared to the empty vector control cell lines (Figure 4(b)). In agreement with enhanced shedding of the ectodomain, we identified higher levels of the 40 kDa intracellular domain in the MMP-7 expressing cell lines compared to the control (Figure 4(b)). These data demonstrate that MMP-7 mediates E-cadherin processing in nontransformed epithelial cell lines.

Bottom Line: Previously, we demonstrated that MMP-7, a protease implicated in mammary and intestinal tumor growth, can process the adherens junction component E-cadherin.This observation leads us to test whether MMP-7 processing of E-cadherin could directly impact cell proliferation in nontransformed epithelial cell lines (MDCK and C57MG).Our goal was to investigate the possibility that MMP-7 produced by cancer cells may have effects on adjacent normal epithelium.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, 734 PRB 2220 Pierce Ave, Nashville, TN 37232, USA.

ABSTRACT
Perturbations in cell-cell contact machinery occur frequently in epithelial cancers and result in increased cancer cell migration and invasion. Previously, we demonstrated that MMP-7, a protease implicated in mammary and intestinal tumor growth, can process the adherens junction component E-cadherin. This observation leads us to test whether MMP-7 processing of E-cadherin could directly impact cell proliferation in nontransformed epithelial cell lines (MDCK and C57MG). Our goal was to investigate the possibility that MMP-7 produced by cancer cells may have effects on adjacent normal epithelium. Here, we show that MMP-7 processing of E-cadherin mediates, (1) loss of cell-cell contact, (2) increased cell migration, (3) a loss of epithelial cell polarization and (4) increased cell proliferation via RhoA activation. These data demonstrate that MMP-7 promotes epithelial cell proliferation via the processing of E-cadherin and provide insights into the molecular mechanisms that govern epithelial cell growth.

No MeSH data available.


Related in: MedlinePlus