Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer.
Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer.
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人乳头瘤病毒 E7 癌蛋白增加 RRM2 表达促进宫颈癌血管生成
DOI：
10.1038/bjc.2013.817
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发表时间：
2014-02-18
影响因子：
8.8
通讯作者：
Li, H.
中科院分区：
文献类型：
--
作者：
Wang, N.;Zhan, T.;Ke, T.;Huang, X.;Ke, D.;Wang, Q.;Li, H.
背景：本研究的目的是证实RRM 2作为HPVE 7的一个新靶点参与宫颈癌血管生成。方法：采用RT-qPCR、Western blot和免疫组化方法分析宫颈癌组织和细胞系中RRM 2的基因表达。荧光素酶报告基因测定用于确定各种RRM 2启动子的活性。ELISA法检测VEGF的表达。使用人脐静脉内皮细胞在体外评估RRM 2介导的由HPVE 7诱导的宫颈癌细胞中的毛细血管形成。通过流式细胞术证实RRM 2在宫颈癌细胞中诱导的ROS。结果：RRM 2作为HPVE 7的下游靶点，通过E7-pRb相互作用和E2 F与RRM 2启动子区的结合，在转录水平上上调RRM 2的表达。免疫组化结果显示，宫颈癌组织中RRM 2和HPVE 7的表达水平呈正相关。在功能上，RRM 2过表达通过激活宫颈癌细胞中的ERK 1/2信号通路增强HIF-1α和VEGF的表达，并且与宫颈癌组织中微血管密度的增加显著相关。在体外，HPVE 7刺激RRM 2依赖的毛细血管形成的HUVECs，和RRM 2增强血管生成是VEGF依赖性的。RRM 2激活的ERK 1/2通路是通过产生ROS介导的。结论：HPVE 7可诱导RRM 2表达上调，从而通过ROS-ERK 1/2-HIF-1α-VEGF诱导的血管生成促进宫颈癌的发生。因此，RRM 2活性的抑制可能是人宫颈癌的一种新的治疗策略。
Background:The purpose of this study was to confirm that RRM2 as a novel target of HPVE7 involved in cervical cancer angiogenesis.Methods:Gene expression was analysed by RT-qPCR, western blot and immunohistochemistry in cervical cancer tissue and cell lines. Luciferase reporter assay was used to determine the activities of various RRM2 promoters. Secreted VEGF was measured by ELISA. RRM2-mediated capillary tube formation induced by HPVE7 in cervical cancer cells were evaluated using human umbilical vein endothelial cells in vitro. ROS induced by RRM2 in cercal cancer cells was confirmed by flow cytometry. The growth of cervical cancer cell overexpression RRM2 was examined by nude mouse xenograft.Results:RRM2 as a novel downstream target for HPVE7 was upregulated by it at the transcriptional level through the E7-pRb interaction and binding of E2F to the RRM2 promoter region. Immunohistochemical analysis showed that the level of RRM2 positively correlated with the HPVE7 level in human cervical cancer. Functionally, overexpression of RRM2 enhanced the expression of HIF-1α and VEGF via activation of the ERK1/2 signalling pathway in cervical cancer cells, and significantly associated with increased microvessel densities in cervical cancer tissues. In vitro, HPVE7 stimulated RRM2-dependent capillary tube formation by HUVECs, and RRM2-enhanced angiogenesis was VEGF dependent. RRM2-activated ERK1/2 pathway was mediated through production of ROS. In the xenograft mouse model, overexpression of RRM2 in cervical cancer cells enhanced tumour growth as well as microvessel densities.Conclusion:HPVE7 induces upregulation of RRM2, which then promotes cervical carcinogenesis via ROS-ERK1/2-HIF-1α-VEGF-induced angiogenesis. Thus, the inhibition of RRM2 activity may be a novel therapeutic strategy for human cervical cancer.
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影响因子：
4.7
作者：
Kuner, Ruprecht;Vogt, Markus;Hoppe-Seyler, Felix
通讯作者：
Hoppe-Seyler, Felix
DOI：
10.1073/pnas.0505337102
发表时间：
2005-08-09
影响因子：
11.1
作者：
Huh, KW;DeMasi, J;Münger, K
通讯作者：
Münger, K
影响因子：
3.3
作者：
Drigotas, Martynas;Affolter, Annette;Brieger, Juergen
通讯作者：
Brieger, Juergen
影响因子：
3.8
作者：
Policht FA;Song M;Sitailo S;O'Hare A;Ashfaq R;Muller CY;Morrison LE;King W;Sokolova IA
通讯作者：
Sokolova IA
影响因子：
11.5
作者：
Ressler, Sigrun;Scheiden, Rene;Zwerschke, Werner
通讯作者：
Zwerschke, Werner