Higher CXCL16 exodomain is associated with aggressive ovarian cancer and promotes the disease by CXCR6 activation and MMP modulation

Ovarian cancer (OvCa) is the leading cause of death from gynecological malignancies. Five-year survival rate of OvCa ranges from 30–92%, depending on the spread of disease at diagnosis. Role of chemokines is well appreciated in cancer, including OvCa. However, their precise role is understudied. Here, we show clinical and biological significance of CXCR6-CXCL16 and ADAM10 in OvCa. Expression of CXCR6 and N-terminal CXCL16 was significantly higher in serous carcinoma tissues compared to endometrioid. OvCa cells (SKOV-3 and OVCAR-3) also showed higher expression of CXCR6 than normal ovarian epithelial cells (IOSE-7576) while CXCL16 was higher in SKOV-3 than IOSE-7576. Furthermore, N-terminal CXCL16 was higher in conditioned media of OvCa cells than IOSE-7576. Compared to OVCAR-3, SKOV-3 cells, which had higher CXCL16, expressed significantly higher transcripts of ADAM10, a protease that cleaves CXCL16. OVCAR-3 cells showed higher CXCR6 specific migration whereas SKOV-3 cells showed more invasion. Difference in invasive potential of these cells was due to modulation of different MMPs after CXCL16 stimulation. Higher CXCR6 expression in serous papillary carcinoma tissues suggests its association with aggressive OvCa. Increased migration-invasion towards CXCL16 implies its role in metastatic spread. Therefore, CXCR6-CXCL16 axis could be used to differentiate between aggressive versus non-aggressive disease and as a target for better prognosis.