Overexpression of CD157 Contributes to Epithelial Ovarian Cancer Progression by Promoting Mesenchymal Differentiation

Abstract

Epithelial ovarian carcinoma (EOC) is an aggressive tumor often diagnosed at an advanced stage, when there is little or no prospect of cure. Despite advances in surgical and chemotherapeutic strategies, only marginal improvements in patient outcome have been obtained. Hence, unraveling the biological mechanisms underpinning EOC progression is critical for improving patients’ survival. Recently, we reported that CD157 (an ectoenzyme regulating leukocyte diapedesis) is expressed in EOC and that high expression of the molecule is negatively correlated with the disease outcome in patients. Here, we demonstrate that forced overexpression of CD157 in OVCAR-3, TOV-21G, A2780 and OV-90 ovarian cancer cell lines promotes morphological and phenotypic changes characterized by disruption of intercellular junctions, downregulation of epithelial markers and upregulation of mesenchymal ones. These changes in cell shape and phenotype bring to reduced sensitivity to anoikis, increased anchorage-independent growth, cell motility and mesothelial invasion. Conversely, knockdown of CD157 in OV-90 and OC314 cells reverts the mesenchymal phenotype and reduces the cells’ migratory potential. Transcriptome profiling analysis highlighted 378 significantly differentially expressed genes, representing the signature of CD157-overexpressing OVCAR-3 and OV-90 cells. The modulation of selected genes translates into alteration of protein expression that give cells a highly malignant phenotype. The overall picture deduced from the analysis of the modulated transcripts is that high expression of CD157 strengthens a number of biological processes favoring tumor progression (including development and cell motility), and weakens several biological processes hindering tumor progression (such as apoptosis, cell death and response to stress). Together, these findings implicate CD157 in the progression of EOC to metastatic disease and suggest that CD157 may represent a valuable therapeutic target.

Binding of CD157 Protein to Fibronectin Regulates Cell Adhesion and Spreading

“…As expected, CD157 knockdown did not completely prevent cell adhesion to ECM proteins because of the existence of compensatory molecular interactions that dampen the effects of CD157 deficiency. Notably, the opposite effects were observed in ovarian cancer cells in which exogenous expression of CD157 resulted in increased cell spreading and cytoskeletal organization, leading to improved tumor cell motility and dissemination (15).…”

“…inflammatory diseases and cancer), where the composition of the extracellular matrix dictates the final outcome. For example, in ovarian cancer, the CD157-ECM interaction occurring in the peritoneal cavity rescues cells from anoikis and promotes their migration and metastatic dissemination, ultimately enhancing tumor aggressiveness (15).…”

“…CD157 expression was silenced by lentiviral delivery of short hairpin RNA (shRNA) targeting BST-1 mRNA (target sequences 5Ј-GAGTCAGACTGCTTGTATA-3Ј (shCD157) and scramble sequence 5Ј-TTCTCCGAACGTGTCACGTT-3Ј) as described previously (15,21). Transduced cells were selected in 2 g/ml puromycin (Santa Cruz Biotechnology) for 3 days.…”

“…It became clear that CD157 could induce a variety of cellular responses both in leukocytes and in ovarian cancer cells, including changes in morphology, spreading, adhesion, motility, and transmigration. These activities of CD157 are apparently unrelated to its enzymatic functions (13)(14)(15). So far, the efforts to unravel the nonenzymatic functions of CD157 have been hampered by the lack of a known nonsubstrate ligand, whose identification has proved elusive.…”

The ADP-ribosyl cyclases - the current evolutionary state of the ARCs

“…This dynamic interplay between Bst1 and integrins is instrumental in controlling leukocyte adhesion to extracellular matrix proteins, migration and diapedesis. The link between Bst1 and cell mobility extends beyond and has been found to regulate tumor cell progression and transition to a mesenchymal phenotype with increased mobility in ovarian epithelial cancer cells (55). The current evidence is that the functions of Bst1 in cell motility are receptorial and catalysis-independent.…”