Alterations in the expression of cancer associated mediators in H-ras transformed murine fibroblast cells

The progression of cancer is characterized by the alteration in key cancer associated activities. This study investigates the expression of proliferation and proinflammatory linked proteins in H-ras transformed marine fibroblast cells. The proteins examined include spermidine/spermine N1-acetyltransferase (SSAT), ornithine decarboxylase (ODC), inducible nitric oxide (iNOS), cyclooxygenase-2 (COX-2), matrix metalloproteinases (MMPs), and associated mediators of MMP activity which include extracellular matrix metalloproteinase inducer (EMMPRIN), reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), and TIMPs (tissue inhibitors of MMPs). Treatment of NR3 cells (H-ras transformed, benign tumor forming) with phorbol-12-myristate acetate (PMA) resulted in an induction of SSAT protein expression, whereas SSAT expression was unaltered in 10T ½ cells (non-transformed). Studies investigating the possible signal transduction pathways involved in the alteration of SSAT protein expression suggests a possible role for protein kinase-C (PKC), mitogen activated protein (MAP) kinase, and phosphatidylinositol-3-kinase (P-I-3 kinase) pathways. The effects of oncostatin M (OSM) on MMPs and associated mediators were also examined in NR3 cells. OSM resulted in an induction of MMP-9 and MMP-2 activity in the transformed cells, with a possible involvement of the P-I-3 kinase pathway and PKC pathways, respectively. OSM treatment on NR3 cells also resulted in an induction of EMMPRIN, TIMP-1 and TIMP-2, with possible involvement of specific proteins of the JAK/STAT pathway. Various other proteins associated with proliferation and proinflammatory was also investigated in transformed and non-transformed cells. Tumor necrosis factor-α (TNF-α), iNOS, COX-2, and ODC protein expression were all elevated in NR3 cells in response to OSM, whereas only COX-2 expression was elevated in the non-transformed cells. The altered expression and regulation of the cancer associated proteins represents an aspect of the altered cellular growth program inherent to H-ras transformed cells.