Abstract
Silencing of Fra-1, a component of the dimeric transcription factor, activator protein-1 (AP-1), inhibits mRNA expression of c-met and cd44 in rat mesothelioma cells and is causally linked to maintenance of the transformed phenotype. However, the mechanisms of Fra-1 regulation and Fra-1 regulated gene expression in human malignant mesothelioma (MM) are unclear. We first show in a panel of human MM cells that Fra-1 mRNA expression in MM is complex and regulated by extracellular signal-regulated kinase (ERK1, ERK2), Src, and phosphatidyl-inositol-3-kinase (PI3K) pathways in a tumor-specific fashion. Cell lines with PI3K-dependent Fra-1 expression were SV40 positive and expressed the lowest basal Fra-1 levels. Levels of Fra-1 expression correlated with amounts of CD44 expression that were greater in simian virus 40 negative (SV40-) MM cells. Using dominant negative (dn), short hairpin (sh) and small interference (si) RNA constructs, we next demonstrate that expression of CD44, the principal hyaluronic receptor in MMs, correlates with Fra-expression in both simian virus 40 positive (SV40+) and SV40- MMs. Moreover, both Fra-1 and CD44 expression are linked to cell migration in SV40- MM cells. Lastly, in contrast to normal lung tissue, tissue microarrays revealed that Fra-1 was expressed in 33 of 34 human MMs, and that all CD44+ tumors were SV40-. These results suggest that Fra-1 is associated with cell migration in human MMs and that Fra-1 modulation of CD44 may govern migration of selected MMs.
Highlights
Malignant mesothelioma (MM) is an insidious tumor associated historically with occupational exposure to asbestos [1,2]
Inhibition of PI3K, Src or the ERK1/2 pathway diminishes Fra-1 expression, transactivation and protein levels in human MM cells in a tumor-specific manner We first focused on whether heterogeneous pathways of Fra-1 regulation occurred in human MM cells using inhibition of upstream signaling cascades
We further showed that shFra-1 in the simian virus 40 (SV40)- line reduced CD44 expression using immunochemistry and CSLM, whereas the SV40+ line had low basal levels of CD44 (Figure 4B)
Summary
Malignant mesothelioma (MM) is an insidious tumor associated historically with occupational exposure to asbestos [1,2]. The average survival of patients is less than 1 year after initial diagnosis of MM, and no successful treatment options exist for the majority of patients [1,3]. These pleomorphic tumors are unique in that they have a long latency period (average of 30+ years) and various pathologies (epithelial, sarcomatous and mixed) that complicate their diagnosis and may govern their prognosis [1,3]. The mechanisms of development of MM are obscure, the initiation of signaling events after interaction of mesothelial cells with asbestos fibers or infection by SV40 may result in transactivation of genes governing cell (page number not for citation purposes). The transcription factor, activator protein-1 (AP1) consists of members of the Jun (c-Jun, JunD, JunB) and Fos (c-Fos, FosB, Fra-1, Fra-2) family of early response protooncogenes [10,11] and is a major target of asbestosinduced cell signaling via activation of mitogen activated protein kinases (MAPK) [12,13]
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