Serum bradykinin levels as a diagnostic marker in cervical cancer with a potential mechanism to promote VEGF expression via BDKRB2

Bradykinin (BK) is one of the kinin peptides and preferentially binds to bradykinin B2 receptor (BDKRB2). A recent study indicated that BK played an important role in the occurrence and progression of cancer. In this study, we evaluated the serum BK levels in 130 cervical cancer (CC) cases (including 65 cases with pre and postsurgery paired samples, another 65 cases with only presurgery samples), 35 cervical intraepithelial neoplasia (CIN) cases (pre and postsurgery paired) and 35 control cases. We found that BK was overexpressed in patients with CC compared to patients with CIN and the control group. When combined with squamous cell carcinomarelated antigen (SCCA), the diagnostic efficacy of BK was prominently enhanced. Moreover, we detected the expression level of the BK receptor BDKRB2 in CC, CIN and normal cervical tissues and observed a higher expression in the CC and CIN tissues than in the normal cervix. We then explored the possible mechanisms of action of BK in promoting the progression of CC. When BK was added to the cell culture medium, human umbilical vein endothelial cell (HUVEC) angiogenesis increased and vascular endothelial growth factor (VEGF) expression in CC cell lines was also elevated. The BK antagonist, HOE140, exerted an opposite effect. The knockdown or the overexpression of BDKRB2 in CC cell lines further confirmed its oncogenic role in angiogenesis. Taken together, the findings of this study suggest that BK may be a diagnostic biomarker for CC and may notably improve the diagnostic efficacy when combined with SCCA. BK promotes the progression of CC by upregulating the expression of VEGF via BDKRB2 and subsequently facilitating angiogenesis.