Fig 1: Overexpression or knockdown of BDKRB2 enhances or suppresses the expression of VEGF in CC cells, respectively. (A) BDKB2R overexpression and knockdown in the SiHa and HeLa cells was established and the transfection efficiency was examined by western blot analysis. A total of 10 μM of BK was added to the supernatant of all these cells. The corresponding VEGF expression was detected simultaneously. (B) The established cells were examined at the mRNA level. (C and D) BDKB2R overexpression in CC cells led to a higher VEGF expression and BDKB2R knockdown in CC cells led to a lower VEGF expression at the mRNA level and in culture supernatants. *P<0.05, **P<0.01 and ***P<0.001. BDKRB2, bradykinin B2 receptor; CC, cervical cancer; VEGF, vascular endothelial growth factor.
Fig 2: BDKRB2 regulates tumor growth in tumor-bearing mice. (A) Survival rates of SiHa-oe (n=7), SiHa-con (n=6) and SiHa-sh (n=7) tumor-bearing mice over time. The survival time of SiHa-sh-B2R tumor-bearing mice was significantly longer than that of the SiHa-con group (P=0.024) and the SiHa-oe-B2R group (P=0.003). (B) Tumor growth volumes were measured and calculated in each group every week. Volume = ab2/2. (C) The corresponding fluorescence intensity was monitored every 2 weeks and quantitative analyzed with ROI tools of live Imaging software 4.0. (D) Typical fluorescence images were displayed at 4 weeks and 6 weeks following inoculation. (E) Representative IHC staining images of B2R, VEGF and CD31 in tumor sections from mice in the 3 groups. The black arrows indicate the neovascularization in the tumor margin. The mice bearing B2R-overexpressing tumors exhibited a significantly more rapid tumor growth, a shorter survival and more angiogenesis. *P<0.05 and **P<0.01.
Fig 3: BK promotes angiogenesis and upregulates VEGF expression in CC cells. (A) Representative images of tube formation experiment of HUVECs cultured with BK or HOE140. (B) The total tube length was quantified and statistics analysis was conducted. BK promoted angiogenesis and HOE140 played an inhibitory role. (C) The expression level of BDKRB2 was higher in the CC cell lines, SiHa and HeLa, and lower in the CIN cell line, S12. (D-F). BK upregulated the expression of VEGF in the SiHa and HeLa cells at the protein level and mRNA level, and in culture supernatants. HOE140 inversely suppressed VEGF expression. *P<0.05, **P<0.01 and ***P<0.001, n.s. non-statistical significance. BK, bradykinin; CC, cervical cancer; CON, control; VEGF, vascular endothelial growth factor.
Fig 4: BDKRB2 is overexpressed in cervical cancer tissues. (A) BDKRB2 was significantly upregulated in CC vs. normal samples in one dataset (Scotto Cervix Statistics) of the Oncomine online database (P<0.05). (B) The overexpression of BDKRB2 was further verified in CC tissues (n=15) and normal cervical tissues (n=9) by RT-qPCR (P<0.05). (C) Typical IHC images of BDKRB2 in CC, CIN and normal tissues. (D) The relevant cartogram of IHC scores of CC (n=44), CIN (n=12) and CON (n=8) tissues. BDKRB2 was notably overexpressed in CC (P<0.05) and CIN tissues (P<0.05) compared to normal cervical tissues. *P<0.05. n.s. non-statistical significance; BDKRB2, bradykinin B2 receptor; CC, cervical cancer; CIN, cervical intraepithelial neoplasia; NC, normal control.
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