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Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer

Wang, N, Zhan, T, Ke, T, Huang, X, Ke, D, Wang, Q, Li, H·2014·British Journal of Cancer
DOI 10.1038/bjc.2013.817PMC PMC3929894
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Figure 1 HPVE7 upregulates expression of RRM2. (A) Western blot (left panel) and real-time RT-PCR analyses of RRM2 in HeLa cells with knockdown of E6 or E6/E7 expression. siNC, negative control siRNA; siE6, siRNA against HPV18 E6; siE7/E6, siRNA against E6 and E7; p53, positive control for siRNA against E6; α-tubulin, loading control for western blot analysis. GAPDH was used as an internal control for quantitative RT-PCR analysis. (B) Western blot (left panel) and quantitative real time RT-PCR analyses of RRM2 in CaSki cells with knockdown of E6 or E6/E7 expression. (C) Western blot (left panel) and quantitative real-time RT-PCR analyses of RRM2 in C33A cells with overexpression of E6 or E7. Cont, transfection with a pcDNA3.1 empty vector as control. (D) The expression level of RRM2 positively correlates with the level of the HPVE7 protein in human cervical cancer (upper panel). The expression levels of RRM2 and HPVE7 in 60 human primary cervical cancer specimens were measured by immunostaining with antibodies specific to RRM2 and HPVE7, and correlated. Positive correlation between RRM2 and HPVE7 levels were determined using a Pearson Chi-Square analysis (P<0.01). The lower panel shows immunostaining images of two representative specimens, one with low (+/−) and the other with high (+/+) expression of RRM2 and HPVE7. H&E staining served as control. The data are shown as mean± s.d. of three separate experiments. NS, no significant difference; *P<0.05; **P<0.01.
Figure 1 HPVE7 upregulates expression of RRM2. (A) Western blot (left panel) and real-time RT-PCR analyses of RRM2 in HeLa cells with knockdown of E6 or E6/E7 expression. siNC, negative control siRNA; siE6, siRNA against HPV18 E6; siE7/E6, siRNA against E6 and E7; p53, positive control for siRNA against E6; α-tubulin, loading control for western blot analysis. GAPDH was used as an internal control for quantitative RT-PCR analysis. (B) Western blot (left panel) and quantitative real time RT-PCR analyses of RRM2 in CaSki cells with knockdown of E6 or E6/E7 expression. (C) Western blot (left panel) and quantitative real-time RT-PCR analyses of RRM2 in C33A cells with overexpression of E6 or E7. Cont, transfection with a pcDNA3.1 empty vector as control. (D) The expression level of RRM2 positively correlates with the level of the HPVE7 protein in human cervical cancer (upper panel). The expression levels of RRM2 and HPVE7 in 60 human primary cervical cancer specimens were measured by immunostaining with antibodies specific to RRM2 and HPVE7, and correlated. Positive correlation between RRM2 and HPVE7 levels were determined using a Pearson Chi-Square analysis (P<0.01). The lower panel shows immunostaining images of two representative specimens, one with low (+/−) and the other with high (+/+) expression of RRM2 and HPVE7. H&E staining served as control. The data are shown as mean± s.d. of three separate experiments. NS, no significant difference; *P<0.05; **P<0.01.CC BY-NC-SA · PubMed Central
Figure 2 HPVE7 induces increased transactivation of the RRM2 promoter. (A) Sequence of the human RRM2 promoter region. (B) MCF-7 cells were co-transfected with a RRM2 promoter luciferase reporter, an expression plasmid for either HPV-16 E7 or an HPV-18 E7 (an empty vector as control, Cont), and a Renilla luciferase plasmid as an internal control. Twenty-four hours after transfection, cells were collected and used for measuring luciferase activities. The data are shown as mean±s.d. from triplicate wells. The experiment was repeated three times. (C) Luciferase assays for the RRM2 promoter (black columns) and the p21 promoter (white columns) in MCF-7 cells with overexpression of HPV16 E6, HPV18 E6 or with empty vector. (D) Luciferase assays for the RRM2 promoter in MCF-7 cells with overexpression of wild-type HPV16 E7 or mutant HPV16 E7 (E7-MUT), which lose the ability to bind to pRb. Cont, empty vector control. (E) Schematic diagram of the RRM2 promoter luciferase reporter genes. WT, wild type RRM2-Luc reporter; MUT, mutant RRM2-Luc with two consensus E2F-binding sites deleted. (F) Luciferase assays for either the wild-type RRM2 promoter (WT) or a mutant RRM2 promoter with a deletion of the E2F-binding site (MUT) in MCF-7 cells with overexpression of HPV-16 E7. Cont, empty vector control. NS, no significant difference; *P<0.05, **P<0.01.
Figure 2 HPVE7 induces increased transactivation of the RRM2 promoter. (A) Sequence of the human RRM2 promoter region. (B) MCF-7 cells were co-transfected with a RRM2 promoter luciferase reporter, an expression plasmid for either HPV-16 E7 or an HPV-18 E7 (an empty vector as control, Cont), and a Renilla luciferase plasmid as an internal control. Twenty-four hours after transfection, cells were collected and used for measuring luciferase activities. The data are shown as mean±s.d. from triplicate wells. The experiment was repeated three times. (C) Luciferase assays for the RRM2 promoter (black columns) and the p21 promoter (white columns) in MCF-7 cells with overexpression of HPV16 E6, HPV18 E6 or with empty vector. (D) Luciferase assays for the RRM2 promoter in MCF-7 cells with overexpression of wild-type HPV16 E7 or mutant HPV16 E7 (E7-MUT), which lose the ability to bind to pRb. Cont, empty vector control. (E) Schematic diagram of the RRM2 promoter luciferase reporter genes. WT, wild type RRM2-Luc reporter; MUT, mutant RRM2-Luc with two consensus E2F-binding sites deleted. (F) Luciferase assays for either the wild-type RRM2 promoter (WT) or a mutant RRM2 promoter with a deletion of the E2F-binding site (MUT) in MCF-7 cells with overexpression of HPV-16 E7. Cont, empty vector control. NS, no significant difference; *P<0.05, **P<0.01.CC BY-NC-SA · PubMed Central
Figure 3 RRM2 mediates HPVE7-induced VEGF expression in cervical cancer cells. (A) C33A and HeLa cells were transiently transfected with a RRM2 expression plasmid. Cells with mock transfection or transfected with the pcDNA3.1 empty vector served as controls. Left panel, the level of secreted VEGF in the conditioned media derived from transfected C33A or HeLa cells was determined by ELISA. Right panel, the expression level of VEGF mRNA in transfected cells was determined by quantitative real time RT-PCR. The data are shown as mean±s.d. from triplicate wells. The experiment was repeated three times. (B) C33A cells were transfected with a HPV16 E7 expression plasmid, and a RRM2 siRNA or a control siRNA. Left panel, ELISA data for the level of secreted VEGF in the conditional media from transfected cells. Right panel, the expression level of VEGF mRNA was determined by quantitative real time RT-PCR. (C) HeLa cells were transfected with a HPV18 E7 siRNA or a control siRNA followed by co-transfection with a RRM2 expression plasmid or the control empty vector. Left panel, ELISA data for the level of secreted VEGF in the conditional media from transfected cells; right panel, quantitative real time RT-PCR data for the expression level of VEGF mRNA. NS, no significant difference; *P<0.05, **P<0.01.
Figure 3 RRM2 mediates HPVE7-induced VEGF expression in cervical cancer cells. (A) C33A and HeLa cells were transiently transfected with a RRM2 expression plasmid. Cells with mock transfection or transfected with the pcDNA3.1 empty vector served as controls. Left panel, the level of secreted VEGF in the conditioned media derived from transfected C33A or HeLa cells was determined by ELISA. Right panel, the expression level of VEGF mRNA in transfected cells was determined by quantitative real time RT-PCR. The data are shown as mean±s.d. from triplicate wells. The experiment was repeated three times. (B) C33A cells were transfected with a HPV16 E7 expression plasmid, and a RRM2 siRNA or a control siRNA. Left panel, ELISA data for the level of secreted VEGF in the conditional media from transfected cells. Right panel, the expression level of VEGF mRNA was determined by quantitative real time RT-PCR. (C) HeLa cells were transfected with a HPV18 E7 siRNA or a control siRNA followed by co-transfection with a RRM2 expression plasmid or the control empty vector. Left panel, ELISA data for the level of secreted VEGF in the conditional media from transfected cells; right panel, quantitative real time RT-PCR data for the expression level of VEGF mRNA. NS, no significant difference; *P<0.05, **P<0.01.CC BY-NC-SA · PubMed Central
Figure 4 RRM2 is involved in cervical cancer angiogenesis in vitro and in vivo. (A) Results from in vitro matrigel-based angiogenesis assays by HUVECs with conditioned media from C33A cells transfected with pcDNA-HPV18 E7 with or without RRM2 siRNA. Representative images (left panel) and mean numbers of mature tube-forming structures (right panel) at × 100 magnification. HUVECs (1 × 104 cells per well) were seeded onto the surface of 96-well cell culture plates precoated with matrigel and then incubated at 37 °C for 8 h in the conditioned media derived from transfected C33A cells. The data presented are representative of three separate experiments. (B) Application of a VEGF antibody (400 ng ml−1) to neutralise VEGF in three conditioned media abrogated RRM2-enhanced capillary tube formation. (C) Immunohistochemical analysis of 60 cervical cancer samples stained with anti-RRM2 and anti-CD31 antibodies (left panel). Representative images of weak RRM2 expression samples (+/− n=24) and strong RRM2 expression samples (+/+ n=36) are shown. H&E staining served as control. Original magnification, × 100. The data on CD31-positive microvessel densities were plotted in the right panel. Microvessel densities were significantly higher in cancer samples with strong RRM2 expression than that with weak expression. Bars indicate the mean number of vessels. **P<0.01.
Figure 4 RRM2 is involved in cervical cancer angiogenesis in vitro and in vivo. (A) Results from in vitro matrigel-based angiogenesis assays by HUVECs with conditioned media from C33A cells transfected with pcDNA-HPV18 E7 with or without RRM2 siRNA. Representative images (left panel) and mean numbers of mature tube-forming structures (right panel) at × 100 magnification. HUVECs (1 × 104 cells per well) were seeded onto the surface of 96-well cell culture plates precoated with matrigel and then incubated at 37 °C for 8 h in the conditioned media derived from transfected C33A cells. The data presented are representative of three separate experiments. (B) Application of a VEGF antibody (400 ng ml−1) to neutralise VEGF in three conditioned media abrogated RRM2-enhanced capillary tube formation. (C) Immunohistochemical analysis of 60 cervical cancer samples stained with anti-RRM2 and anti-CD31 antibodies (left panel). Representative images of weak RRM2 expression samples (+/− n=24) and strong RRM2 expression samples (+/+ n=36) are shown. H&E staining served as control. Original magnification, × 100. The data on CD31-positive microvessel densities were plotted in the right panel. Microvessel densities were significantly higher in cancer samples with strong RRM2 expression than that with weak expression. Bars indicate the mean number of vessels. **P<0.01.CC BY-NC-SA · PubMed Central
Figure 5 RRM2 mediates HPVE7-induced activation of the ERK1/2 signalling pathway and increases of HIF-1α and VEGF expression. (A) RRM2-induced HIF-1α protein expression was abolished by inhibition of the ERK1/2 signalling pathway by U0126. C33A cells transfected with a RRM2 expression plasmid or a control empty vector were treated with 10 μM U0126 or vehicle control for 16 h. The expression levels of phosphorylated ERK1/2 and HIF-1α were examined by western blot analysis. t-ERK, total ERK levels used as loading control; GAPDH, another loading control. (B) RRM2-induced VEGF expression was abolished by inhibition of the ERK1/2 signalling pathway by U0126. The level of secreted VEGF in the conditioned media was measured by an ELISA assay. The data presented are representative of three independent experiments. (C) C33A cells were transfected with pcDNA-HPV16E7, followed by co-transfection with a RRM2 siRNA (siRRM2) or a control siRNA (siNC) for another 24 h. Cell lysates were used for western blot analysis for phosphorylated ERK1/2 and HIF-1α protein levels. (D) HeLa cells were transfected with a HPV18 E7 siRNA (siE7) or a control siRNA (siNC), followed by co-transfection with pcDNA-RRM2 for another 24 h. Cell lysates were used for western blot analysis for phosphorylated ERK1/2 and HIF-1α protein levels. **P<0.01.
Figure 5 RRM2 mediates HPVE7-induced activation of the ERK1/2 signalling pathway and increases of HIF-1α and VEGF expression. (A) RRM2-induced HIF-1α protein expression was abolished by inhibition of the ERK1/2 signalling pathway by U0126. C33A cells transfected with a RRM2 expression plasmid or a control empty vector were treated with 10 μM U0126 or vehicle control for 16 h. The expression levels of phosphorylated ERK1/2 and HIF-1α were examined by western blot analysis. t-ERK, total ERK levels used as loading control; GAPDH, another loading control. (B) RRM2-induced VEGF expression was abolished by inhibition of the ERK1/2 signalling pathway by U0126. The level of secreted VEGF in the conditioned media was measured by an ELISA assay. The data presented are representative of three independent experiments. (C) C33A cells were transfected with pcDNA-HPV16E7, followed by co-transfection with a RRM2 siRNA (siRRM2) or a control siRNA (siNC) for another 24 h. Cell lysates were used for western blot analysis for phosphorylated ERK1/2 and HIF-1α protein levels. (D) HeLa cells were transfected with a HPV18 E7 siRNA (siE7) or a control siRNA (siNC), followed by co-transfection with pcDNA-RRM2 for another 24 h. Cell lysates were used for western blot analysis for phosphorylated ERK1/2 and HIF-1α protein levels. **P<0.01.CC BY-NC-SA · PubMed Central
Figure 6 RRM2 elicited production of ROS to activate the ERK1/2 pathway, and enhance HIF-1α and VEGF expression. (A) RRM2 increases generation of ROS in cervical cancer cells. C33A or HeLa cells were transfected with a RRM2 expression plasmid (empty vector as control, left panel) or a RRM2 siRNA (siNC, negative control siRNA, right panel) for 48 h. Cells were then incubated with 20 μM DCFHDA in the dark for 30 min at 37 °C, washed in PBS, resuspended in PBS and analysed by flow cytometry. (B) NAC prevents RRM2 induced activation of ERK1/2 (p-ERK) and increases of HIF-1α and VEGF expression. C33A cells were transfected with a RRM2 expression plasmid for 24 h, followed by treatment with an indicated amount of NAC for 24h. Cells were lysed and used for western blot analysis with antibodies against pERK1/2 and HIF-1α. t-ERK, total ERK levels used as loading control; α-tubulin, loading control. The expression level of VEGF in conditioned media was measured by an ELISA assay. *P<0.05.
Figure 6 RRM2 elicited production of ROS to activate the ERK1/2 pathway, and enhance HIF-1α and VEGF expression. (A) RRM2 increases generation of ROS in cervical cancer cells. C33A or HeLa cells were transfected with a RRM2 expression plasmid (empty vector as control, left panel) or a RRM2 siRNA (siNC, negative control siRNA, right panel) for 48 h. Cells were then incubated with 20 μM DCFHDA in the dark for 30 min at 37 °C, washed in PBS, resuspended in PBS and analysed by flow cytometry. (B) NAC prevents RRM2 induced activation of ERK1/2 (p-ERK) and increases of HIF-1α and VEGF expression. C33A cells were transfected with a RRM2 expression plasmid for 24 h, followed by treatment with an indicated amount of NAC for 24h. Cells were lysed and used for western blot analysis with antibodies against pERK1/2 and HIF-1α. t-ERK, total ERK levels used as loading control; α-tubulin, loading control. The expression level of VEGF in conditioned media was measured by an ELISA assay. *P<0.05.CC BY-NC-SA · PubMed Central
Figure 7 RRM2 overexpression promotes the growth and angiogenesis of cervical cancer xenografts in nude mice. (A) C33A-RRM2 and C33A-vector cells were subcutaneously inoculated into the flank of nude mice. Thirty-two days after the inoculation, the mice were killed and tumour tissues were collected. Left panel shows photographs of the tumours. Right panel shows that overexpression of RRM2 increased the tumour size of C33A-RRM2 at the end of experiment. (B) Overexpression of RRM2 significantly enhanced tumour growth as compared with empty vector. The graph shows tumour growth curves in nude mice inoculated with C33A cells with overexpression of RRM2 or cells with the cloning vector. Data are presented as means ±s.d. (n=5). (C) quantitative RT-PCR analysis of RRM2 and VEGF mRNA in C33A-RRM2 and C33A-vector xenografts. Data are shown as mean±s.d. from five mice. (D) Representative images of tumour sections from RRM2-overexpressed cells and control cells immunostained with pERK1/2 and CD31 antibodies (left panel). The level of phosphorylated ERK1/2 was significantly higher in RRM2-overexpression tumours than in control tumours. H&E staining served as control. Right panel, CD31-positive vessel densities were significantly increased in C33A-RRM2 tumour xenografts compared with that from C33A-vector. Data are presented as mean±s.d. (n=5). *P<0.05, **P<0.01.
Figure 7 RRM2 overexpression promotes the growth and angiogenesis of cervical cancer xenografts in nude mice. (A) C33A-RRM2 and C33A-vector cells were subcutaneously inoculated into the flank of nude mice. Thirty-two days after the inoculation, the mice were killed and tumour tissues were collected. Left panel shows photographs of the tumours. Right panel shows that overexpression of RRM2 increased the tumour size of C33A-RRM2 at the end of experiment. (B) Overexpression of RRM2 significantly enhanced tumour growth as compared with empty vector. The graph shows tumour growth curves in nude mice inoculated with C33A cells with overexpression of RRM2 or cells with the cloning vector. Data are presented as means ±s.d. (n=5). (C) quantitative RT-PCR analysis of RRM2 and VEGF mRNA in C33A-RRM2 and C33A-vector xenografts. Data are shown as mean±s.d. from five mice. (D) Representative images of tumour sections from RRM2-overexpressed cells and control cells immunostained with pERK1/2 and CD31 antibodies (left panel). The level of phosphorylated ERK1/2 was significantly higher in RRM2-overexpression tumours than in control tumours. H&E staining served as control. Right panel, CD31-positive vessel densities were significantly increased in C33A-RRM2 tumour xenografts compared with that from C33A-vector. Data are presented as mean±s.d. (n=5). *P<0.05, **P<0.01.CC BY-NC-SA · PubMed Central

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Authors
Wang, N., Zhan, T., Ke, T., Huang, X., Ke, D., Wang, Q., & Li, H.
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2014-01-14
Volume
110
Issue
4
Pages
1034-1044
ISSN
  • 0007-0920
  • 1532-1827
DOI
10.1038/bjc.2013.817
PMC
PMC3929894
Cited by
84
References
1
Language
en
Licence
www.springer.com/tdm (unspecified)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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