URG4促进宫颈癌血管生成的作用及分子机制

It has been well-known that angiogenesis play key roles in development and survival prognosis of cervical cancer. The mechanisms of angiogenesis, however, still remain largely unclear and be lack of molecular markers. Importantly, our recent preliminary data showed that URG4 was upregulated in human cervical cancer tissues than the paired adjacent non-tumor tissues, and significantly upregulated in all of the tested cervical cancer cell lines compared to normal cervical cells. Furthermore, overexpression of URG4 significantly associated with high risk clinical pathology factors and is an independent risk factor for early cervical cancer patients prognosis. Moreover, we found URG4 had the function promoting angiogenesis of cervical cancer in vitro. According to the analysis of cervical cancer chips, we found URG4 promotion angiogenesis in cervical cancer by NF-κB/Wnt pathway.Furthermore we found URG4 activated NF-κB signaling pathway and upregulated angiogenesis-related factors in cervical cancer cells. Accordingly we speculated URG4 promotion angiogenesis in cervical cancer by NF-κB/Wnt pathway.Therefore, in the current study, using in vivo systems and combined with clinical samples, we aim to further investigate the molecular mechanisms and biological effect of URG4 on angiogenesis of cervical cancer cells. These play a role in mechanisms of angiogenesis, meanwhile, would provide a novel and useful prognostic marker and a potential target for human cervical cancer treatment.

大量研究证实血管生成是影响肿瘤发生发展和患者生存预后的重要因素，然而宫颈癌中血管生成的机制尚未明确，而且缺乏相关分子标记物。前期研究中我们发现，URG4在宫颈癌组织及细胞系中的表达都明显高于癌旁组织及正常宫颈上皮细胞，并且高表达URG4与多项高危临床病理因素相关，是早期宫颈癌患者预后的独立危险因素。后续我们在体外实验中发现URG4具有促进宫颈癌血管生成的生物学功能，宫颈癌组织芯片分析结果提示URG4激活NF-κB和或Wnt通路，预试验证实URG4激活NF-κB通路上调VEGF等血管生成相关因子。据此我们提出URG4激活NF-κB和或Wnt通路促进宫颈癌血管生成的可能性。本课题进一步在体内实验系统及临床样本中验证，多层面探讨URG4激活相关信号通路促进宫颈癌细胞血管生成的分子机制，对阐明宫颈癌血管生成机制有重要意义，为宫颈癌患者诊治提供新的靶点和理论依据。

血管生成（Angiogenesis）是恶性肿瘤的重要的恶性表型之一，是肿瘤生长、侵袭和转移的生物学基础，同时也是影响放疗，化疗及靶向治疗的重要因素。临床研究提示：在复发、持续和转移晚期宫颈癌患者中抗血管生成靶向药物联合化疗，可以提高患者的总生存时间。但目前宫颈癌中血管生成的机制尚未明确，而且缺乏相关分子标记物。国内外研究提示细胞增殖上调因子4（upregulator of cell proliferation,URG4）与生理病理进程和诸多人类恶性肿瘤的生物学功能相关，在宫颈癌中尚吴相关研究。.前期研究中我们发现，URG4在宫颈癌组织及细胞系中的表达都明显高于癌旁组织及正常宫颈上皮细胞，并且高表达URG4与多项高危临床病理因素（包括临床分期，肿瘤大小及淋巴结转移）相关，是早期宫颈癌患者预后的独立危险因素。后续我们在体外实验中发现URG4具有促进宫颈癌血管生成的生物学功能，宫颈癌组织芯片分析结果提示URG4激活NF-κB和或Wnt通路，预试验证实URG4激活NF-κB通路上调VEGF等血管生成相关因子。据此我们提出URG4激活NF-κB和或Wnt通路促进宫颈癌血管生成的可能性。.本课题立项后，（1）首先，我们深度挖掘已有宫颈癌临床标本及相关资料数据（基本信息配对），发现URG4的高表达与宫颈癌癌组织外血管内癌栓阳性正相关。（2）继而生物信息学分析提URG4的表达能富集到与肿瘤血管生成的基因集。（3）同时，前期研究生物学实验证实URG4表达与宫颈癌细胞上清诱导的血管生成正相关，进一步分子生物学实验证实URG4通过NF-kB信号通路上调VEGF-A，VEGF-C促进血管生成。（4）在上述基础上，构建动物模型回归到肿瘤组织，验证上述实验结果。.本研究结果，对阐明URG4促进宫颈癌血管生成机制有重要意义，为宫颈癌患者诊治提供新的靶点和理论依据。