Altered matrix metalloproteinase expression associated with oncogene-mediated cellular transformation and metastasis formation

Matrix metalloproteinase expression was examined in a series of mammalian cell lines of varying degrees of malignant progression, The expression of MMP-2 and MMP-9 was found to correlate with ras-mediated cellular transformation and as a function of malignant potential. Altered MMP-2 and MMP-9 expression was found to correlate also in other oncogene transformed cell lines and the level of expression of both MMP-2 and MMP-9 correlated with metastatic potential. Increased expression of both MMP-2 and MMP-9 was also found in cells which constitutively over-express MAP kinase kinase suggesting that one of the consequences of the persistent activation of the MAP kinase pathway is elevated expression of MMP-2 and MMP-9. Additionally, this study demonstrated a correlation between the expression of MMP-3 (stromelysin-l) and the level of ras expressed in cells and with the cells' ability to form tumors and with malignant potential. The existence of a novel 80 kDa caseinase activity which correlates with ras expression and the ability of the cell to form tumors was also demonstrated. The growth status of transformed cells was also found to be important in determining the expression of MMP-2 mRNA but not MMP-9 mRNA expression, and this expression was cell-type specific. This study also demonstrates that oncogenes can interact to influence and to determine the nature of the matrix metalloproteinases expressed and that this interaction results in a tumorigenic phenotype and, most importantly, contributes to the metastatic phenotype. Alterations in the expression and the regulation of MMPs, particularly MMP-2 and MMP-9, constitute an integral part of the altered growth regulatory program found within transformed cells and in particular, in transformed cells capable of malignant progression. (C) 2001 Academic Press.PT: J; CR: BALLIN M, 1988, BIOCHEM BIOPH RES CO, V154, P832 CHADDEE DN, 1995, J BIOL CHEM, V220, P28009 DENHARDT DT, 1987, ONCOGENE, V2, P55 DUFFY M, 1996, ADV CLIN CHEM, V132, P135 EGAN SE, 1987, MOL CELL BIOL, V7, P830 EGAN SE, 1987, SCIENCE, V238, P202 FUKAMI J, 1995, EXP CELL RES, V216, P107 GINGRAS MC, 1990, CANCER RES, V50, P4061 GOODMAN LV, 1989, J BIOL CHEM, V264, P5241 HURTA RAR, 1996, J CELL BIOCHEM, V60, P572 LOCHTER A, 1999, MOL BIOL CELL, V10, P271 MANSOUR SJ, 1994, SCIENCE, V265, P966 MATRISIAN LM, 1992, BIOESSAYS, V14, P455 OETKEN C, 1992, EXP CELL RES, V202, P370 RAY JM, 1994, EUR RESPIR J, V7, P2062 SAMUEL SK, 1992, EMBO J, V11, P1599 SCHWARZ LC, 1988, CANCER RES, V48, P6999 TAYLOR WR, 1992, ONCOGENE, V7, P1383 TUCK AB, 1991, J NATL CANCER I, V83, P485 WITTY JP, 1995, MOL BIOL CELL, V16, P1287 XHANG JY, 1992, CANCER RES, V52, P6682; NR: 21; TC: 10; J9: CELL BIOL INT; PG: 10; GA: 438KZSource type: Electronic(1