PO-176 Hepatocyte growth factor activator inhibitor-2 suppresses human prostate and lung cancer cell invasion and metastasis

Abstract

IntroductionIntegrins are glycosylated transmembrane receptor family proteins, mediate cancer cell to extracellular matrix (ECM) interaction. Integrins are essential for adhesion and migration of cancer cells and frequently associate with poor disease outcome. In addition, glycosylation of integrins modulates receptor and ligand binding affinity. However, the physiological role of glycosylation of integrins remain unclear. Based on our recent findings that disruption of glycosphingolipids triggering loss of α2,6-sialylation Alam et al. 2017 here, we identified integrin α2 as candidate and investigated its potential role in facilitating ovarian cancer metastasis.Material and methodsHypersialylated proteins were identified by lectin-enrichment proteomic analysis. CRISPR-Cas9 mediated site-specific deletion of integrin α2 together with a lentiviral-mediated rescue system were established in four ovarian cancer cell lines (IGROV1, SKOV3, SKOV3ip, and OVCAR4). ECM- and mesothelial cell- adhesion assays were applied to evaluate integrin-mediated in vitro cell adhesion, while a zebrafish transplant model was used to study in vivo cell invasion ability. Finally, integrin expression and sialylation profile were determined in patient-derived matched primary and metastatic ovarian cancer tumour specimens.Results and discussionsProteomic analysis identified integrin α2 as a hypersialylated protein in ovarian cancer cells. Loss of sialylation on N-glycoproteins of cancer cells reduced cell adhesion to collagen type I, fibronectin, and laminin. Furthermore, integrin α2 knockout cancer cells abolished cell adhesion to collagen whereas rescuing integrin α2 expression in those knockout cells fully restored the adhesion ability. We also identified an elevated level of intergin α2 in patient-derived metastatic tumour compared to primary site and tumor-free omentum, indicating a niche for ovarian cancer cells toward omental metastasis.ConclusionOur data demonstrate that α2,6 sialylation on integrin α2 triggers ovarian cancer cell adhesion to metastatic sites. Therefore, blocking sialylation and integrin α2 may be a therapeutic target for preventing ovarian cancer metastasis in the future.