Abstract
The link between oncogenic RAS expression and the acquisition of the invasive phenotype has been attributed to alterations in cellular activities that control degradation of the extracellular matrix. Oncogenic RAS-mediated upregulation of matrix metalloproteinase 2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (uPA) is critical for invasion through the basement membrane and extracellular matrix. The uPA converts cell surface-bound plasminogen to plasmin, a process that is regulated by the binding of plasminogen to specific receptors on the cell surface, however, the identity of the plasminogen receptors that function in this capacity is unclear. We have observed that transformation of cancer cells with oncogenic forms of RAS increases plasmin proteolytic activity by 2- to 4-fold concomitant with a 3-fold increase in cell invasion. Plasminogen receptor profiling revealed RAS-dependent increases in both S100A10 and cytokeratin 8. Oncogenic RAS expression increased S100A10 gene expression which resulted in an increase in S100A10 protein levels. Analysis with the RAS effector-loop mutants that interact specifically with Raf, Ral GDS pathways highlighted the importance of the RalGDS pathways in the regulation of S100A10 gene expression. Depletion of S100A10 from RAS-transformed cells resulted in a loss of both cellular plasmin generation and invasiveness. These results strongly suggest that increases in cell surface levels of S100A10, by oncogenic RAS, plays a critical role in RAS-stimulated plasmin generation, and subsequently, in the invasiveness of oncogenic RAS expressing cancer cells.
Highlights
It is well established that a key requirement for invasion and metastasis of cancer cells is the degradation of both the extracellular matrix (ECM) that surrounds the tumor and the basement membrane which presents the final barrier between the tumor cells and the blood stream [1,2,3,4,5]
Since expression of oncogenic RAS can increase the release of the plasminogen activator, urokinasetype plasminogen activator, cells were assayed both in the presence and absence of exogenous urokinase-type plasminogen activator (uPA)
The first committed step in metastasis, the departure of tumor cells from a solid malignant tumor is controlled by three events, namely: 1) the attachment to and interaction of the tumor cells with components of the ECM and basement membrane: 2) the activation of tumor cell migration and: 3) the activation of local proteolysis
Summary
It is well established that a key requirement for invasion and metastasis of cancer cells is the degradation of both the extracellular matrix (ECM) that surrounds the tumor and the basement membrane which presents the final barrier between the tumor cells and the blood stream [1,2,3,4,5]. Cancer cells that have acquired an invasive phenotype release proteases that attack and digest the protein component of the matrix that would restrict the movement of these malignant cells. These proteases, including the urokinase-type plasminogen activator (uPA) [6, 7], cathepsin B [8] and matrix metalloproteinases (MMPs) [9], have been the subject of intense study in recent years as potential mediators of cancer cell invasion and metastasis. UPA expression in both the tumor and the surrounding stroma has been shown to be a prognostic indicator of survival in various cancers with high expression being associated with poor prognosis [5, 14,15,16,17]
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