Association between αvβ6 integrin expression, elevated p42/44 kDa MAPK, and plasminogen‐dependent matrix degradation in ovarian cancer

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Abstract
Altered expression of αv integrins plays a critical role in tumor growth, invasion, and metastasis. In this study, we show that normal human epithelial ovarian cell line, HOSE, and ovarian cancer cell lines, OVCA 429, OVCA 433, and OVHS-1, expressed αv integrin and associated β1, β3, and β5 subunits, but only ovarian cancer cell lines OVCA 429 and OVCA 433 expressed αvβ6 integrin. The expression of αvβ6 in OVCA 429 and OVCA 433 was far higher than αvβ3 and αvβ5 integrin and correlated with high p42/p44 mitogen activated protein kinase (MAPK) activity and high secretion of high molecular weight urokinase plasminogen activator (HMW-uPA), pro-metalloproteinase 2 and 9 (pro-MMP-9 and pro-MMP-2). In contrast to HOSE and OVHS 1, OVCA 433 and OVCA 429 exhibited approximately 2-fold more plasminogen-dependent [3H]-collagen type IV degradation. Plasminogen-dependent [3H]-collagen IV degradation was inhibited by inhibitor of uPA (amiloride) and MMP (phenanthroline) and by antibodies against uPA or MMP-9 or αvβ6 integrin, indicating the involvement of αvβ6 integrin, uPA and MMP-9 in the process. The αvβ6 correlated increase in HMW-uPA and pro-MMP secretion could be inhibited by tyrosine kinase inhibitor genistein or the MEK 1 inhibitor U0126, consistent with a role of active p42/44 MAPK in the elevation of uPA, MMP-9, and MMP-2 secretion. Under similar conditions, genistein and U0126 inhibited plasminogen-dependent [3H]-collagen type IV degradation. These data suggest that sustained elevation of p42/44 MAPK activity may be required for the co-expression of αvβ6 integrin, which in turn may regulate the malignant potential of ovarian cancer cells via proteolytic mechanisms. J. Cell. Biochem. 84: 675–686, 2002.