食管癌中异常高表达的IGFBP-1 的功能与分子作用机制及其早期诊断价值研究

食管癌缺乏早期诊断血清分子标志物。近期，我们应用两套高通量抗体芯片筛选，同时ELISA实验大样本验证，发现早期食管癌患者血清中IGFBP-1水平异常显著升高，早期诊断效能非常好（ROC曲线下面积0.898），而且，食管癌患者术后血清IGFBP-1明显降低。另外，细胞实验提示，相对于永生化食管上皮细胞，IGFBP-1蛋白在食管癌细胞及其培养上清液均显著升高，且外源性IGFBP-1可明显激活食管癌细胞ERK信号通路。上述系列实验提示，IGFBP-1是食管癌有潜力早期诊断血清分子标志物，是食管癌重要功能蛋白。基于此，本项目拟通过多中心大样本验证与巢式病例对照研究，研究确证血清IGFBP-1作为食管癌早期诊断分子标志物临床价值，同时建立相关细胞模型与动物模型，结合功能研究，深入到分子水平，深刻揭示高表达IGFBP-1在食管癌中作用机制，为IGFBP-1早期诊断分子标志物开发提供扎实基础理论依据。

Esophageal cancer lacks serum biomarker for early diagnosis. Recently, by using two kinds of high-throughput antibody arrays for screening and ELISA assays for large sample validation, we found that serum IGFBP-1 showed significantly elevated levels in patients with esophageal cancer, compared with normal controls, and provided high diagnostic accuracy of early-stage esophageal cancer (area under the curve: 0.898). Moreover, the levels of serum IGFBP-1 dropped after surgical resection of primary tumors in esophageal cancer patients. As for cell experiment, we observed that expression levels of IGFBP-1 protein also increased in esophageal cancer cell and its cell culture supernatant, compared with immortalized esophageal epithelial cells. Interestingly, treatment with recombinant human IGFBP-1 protein could activate ERK signaling pathway in esophageal cancer cell. The above-mentioned results indicate that IGFBP-1 is a potential serum biomarker for the early diagnosis of esophageal cancer, and might be an important functional protein in esophageal cancer. Thus, in this project, we will apply multi-center validation study and nested case-control study to comprehensively evaluate the early diagnostic value of serum IGFBP-1 in esophageal cancer. Meanwhile, we will further establish relevant cell models combined with cell function and molecular biology experiment to reveal the molecular mechanism of high expression of IGFBP-1, which will provide a solid theoretical basis for the development of this biomarker for early diagnosis in esophageal cancer.