Fra-1 governs cell migration via modulation of CD44 expression in human mesotheliomas.
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.
Ramos-Nino
Maria E
ME
Department of Pathology, University of Vermont College of Medicine, Burlington VT 05405, USA. Maria.Ramos@uvm.edu
Blumen
Steven R
SR
Pass
Harvey
H
Mossman
Brooke T
BT
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008168:Lung / Q000378:metabolism; D008654:Mesothelioma / Q000378:metabolism* / Q000821:virology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013539:Simian virus 40; D046888:Tissue Array Analysis; D015533:Transcriptional Activation; D014162:Transfection; D000099169:Fos-Related Antigen 1
D018960:Hyaluronan Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D000099169:Fos-Related Antigen 1