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C-FOS suppresses ovarian cancer progression by changing adhesion.

ABSTRACT: BACKGROUND: C-Fos was initially described as oncogene, but was associated with favourable prognosis in ovarian cancer (OvCa) patients. The molecular and functional aspects underlying this effect are still unknown. METHODS: Using stable transfectants of SKOV3 and OVCAR8 cells, proliferation, migration, invasion and apoptotic potential of c-FOS-overexpressing clones and controls were compared. Adherence to components of the extracellular matrix was analysed in static assays, and adhesion to E-selectin, endothelial and mesothelial cells in dynamic flow assays. The effect of c-FOS in vivo was studied after intraperitoneal injection of SKOV3 clones into SCID mice, and changes in gene expression were determined by microarray analysis. RESULTS: Tumour growth after injection into SCID mice was strongly delayed by c-FOS overexpression, with reduction of lung metastases and circulating tumour cells. In vitro, c-FOS had only weak influence on proliferation and migration, but was strongly pro-apoptotic. Adhesion to components of the extracellular matrix (collagen I, IV) and to E-selectin, endothelial and mesothelial cells was significantly reduced in c-FOS-overexpressing OvCa cells. This corresponds to deregulation of adhesion proteins and glycosylation enzymes in microarray analysis. CONCLUSION: In addition to its known pro-apoptotic effect, c-FOS might influence OvCa progression by changing the adhesion of OvCa cells to peritoneal surfaces.

SUBMITTER: Oliveira-Ferrer L

PROVIDER: S-EPMC3915133 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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c-FOS suppresses ovarian cancer progression by changing adhesion.

Oliveira-Ferrer L L Rößler K K Haustein V V Schröder C C Wicklein D D Maltseva D D Khaustova N N Samatov T T Tonevitsky A A Mahner S S Jänicke F F Schumacher U U Milde-Langosch K K

British journal of cancer 20131205 3

<h4>Background</h4>C-Fos was initially described as oncogene, but was associated with favourable prognosis in ovarian cancer (OvCa) patients. The molecular and functional aspects underlying this effect are still unknown.<h4>Methods</h4>Using stable transfectants of SKOV3 and OVCAR8 cells, proliferation, migration, invasion and apoptotic potential of c-FOS-overexpressing clones and controls were compared. Adherence to components of the extracellular matrix was analysed in static assays, and adhes ...[more]

PMID: 24322891

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Project description:BackgroundPhosphatase of regenerating liver-3 (PRL-3), a protein tyrosine phosphatase, is highly expressed in multiple human cancers and strongly implicated in tumor progression and cancer metastasis. However, the mechanisms by which PRL-3 promotes cancer cell migration, invasion, and metastasis are not very well understood. In this study, we investigated the contribution and molecular mechanisms of PRL-3 in ovarian cancer progression.MethodsPRL-3 protein expression was detected on ovarian cancer tissue microarrays using immunohistochemistry. Stable PRL-3 depleted cell lines were generated using short hairpin RNA (shRNA) constructs. The migration and invasion potential of these cells were analyzed using Transwell and Matrigel assays, respectively. Immunoblotting and immunofluorescence were used to detect protein levels and distribution in PRL-3-ablated cells and the control cells. Cell morphology was observed with hematoxylin-eosin staining and transmission electron microscopy. Finally, PRL-3-ablated and control cells were injected into nude mice for xenograft tumorigenicity assays.ResultsElevated PRL-3 expression was detected in 19% (26 out of 135) of human ovarian cancer patient samples, but not in normal ovary tissues (0 out of 14). Stable depletion of PRL-3 in A2780 ovarian cancer cells resulted in decreased migration ability and invasion activity compared with control parental A2780 cells. In addition, PRL-3-ablated cells also exhibited flattened morphology and extended lamellipodia. To address the possible molecular basis for the altered phenotypes associated with PRL-3 down-regulation, we assessed the expression profiles of various proteins involved in cell-matrix adhesion. Depletion of PRL-3 dramatically enhanced both RNA and protein levels of the cell surface receptor integrin α2, but not its heterologous binding partner integrin β1. Inhibition of PRL-3 also correlated with elevated expression and phosphorylation of paxillin. A pronounced increase in the expression and activation of c-fos, a transcriptional activator of integrin α2, was observed in these PRL-3 knock-down cells. Moreover, forced expression of EGFP-PRL-3 resulted in the suppression of both integrin α2 and c-fos expression in A2780 cells. Significantly, using a xenograft tumor model, we observed a greatly reduced tumorigenicity of A2780 PRL-3 knock-down cells in vivo.ConclusionsThese results suggest that PRL-3 plays a critical role in ovarian cancer tumorigenicity and maintaining the malignant phenotype. PRL-3 may inhibit c-fos transcriptional regulation of integrin α2 signaling. Our results strongly support a role for PRL-3 as a promising therapeutic target and potential early biomarker in ovarian cancer progression.

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C-FOS suppresses ovarian cancer progression by changing adhesion.

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c-FOS suppresses ovarian cancer progression by changing adhesion.

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