Identification of Human Complement Factor B as a Novel Biomarker Candidate for Pancreatic Ductal Adenocarcinoma
Identification of Human Complement Factor B as a Novel Biomarker Candidate for Pancreatic Ductal Adenocarcinoma
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DOI：
10.1021/pr5002719
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发表时间：
2014-11-01
影响因子：
4.4
通讯作者：
Paik, Young-Ki
中科院分区：
文献类型：
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作者：
Lee, Min Jung;Na, Keun;Paik, Young-Ki
胰腺癌（PC；胰腺导管腺癌）在世界范围内具有显著的发病率和死亡率。虽然碳水化合物抗原（CA） 19-9已被认为是一种PC生物标志物，但由于其敏感性和特异性较低，不常用于一般筛查。因此，迫切需要开发一种新的生物标志物，用于癌症早期PC的诊断。为了寻找一种新的血清学PC生物标志物，我们对185份来自健康供体和5种疾病组(包括慢性胰腺炎（CP）、PC和其他癌症（如肝细胞癌、胆管癌和胃癌）患者的汇总或个体血浆进行了综合蛋白质组学分析，并确定补体因子b （CFB）作为PC诊断的候选血清学生物标志物。免疫印迹分析显示，CFB在PC患者血浆样品中的表达比非PC患者血浆样品高两倍以上。免疫沉淀结合质谱分析证实了CFB在PC样品中的分子特性和高表达。CFB对其他类型消化道肿瘤的特异性明显高于CA 19-9，对PC患者和非PC患者的特异性也明显高于CA 19-9 （p < 0.0001）。在接受者操作者特征曲线分析中，CFB的曲线下面积为0.958 (95% CI: 0.956 ~ 0.959)，而ca19 -9的曲线下面积为0.833 （95% CI: 0.829 ~ 0.837）。此外，CFB的y指数远高于CA 19-9 (71.0 vs 50.4)，表明CFB在区分PC与CP和其他胃肠道肿瘤方面优于CA 19-9。免疫沉淀和qRT-PCR实验进一步支持了这一观点，表明CFB在PC细胞系中的表达高于正常细胞系。CFB联合CA 19-9诊断PC与非PC的敏感性（90.1 vs 73.1%）明显高于单独CFB，特异性相似（97.2 vs 97.9%）。因此，我们的研究结果确定CFB是一种新的血清学PC生物标志物候选物，值得进一步大规模验证其在胰腺癌发生分子机制中的作用。
Pancreatic cancer (PC; pancreatic ductal adenocarcinoma) is characterized by significant morbidity and mortality worldwide. Although carbohydrate antigen (CA) 19-9 has been known as a PC biomarker, it is not commonly used for general screening because of its low sensitivity and specificity. Therefore, there is an urgent need to develop a new biomarker for PC diagnosis in the earlier stage of cancer. To search for a novel serologic PC biomarker, we carried out an integrated proteomic analysis for a total of 185 pooled or individual plasma from healthy donors and patients with five disease groups including chronic pancreatitis (CP), PC, and other cancers (e.g., hepatocellular carcinoma, cholangiocarcinoma, and gastric cancer) and identified complement factor b (CFB) as a candidate serologic biomarker for PC diagnosis. Immunoblot analysis of CFB revealed more than two times higher expression in plasma samples from PC patients compared with plasma from individuals without PC. Immunoprecipitation coupled to mass spectrometry analysis confirmed both molecular identity and higher expression of CFB in PC samples. CFB showed distinctly higher specificity than CA 19-9 for PC against other types of digestive cancers and in discriminating PC patients from non-PC patients (p < 0.0001). In receiver operator characteristic curve analysis, CFB showed an area under curve of 0.958 (95% CI: 0.956 to 0.959) compared with 0.833 (95% CI: 0.829 to 0.837) for CA 19-9. Furthermore, the Y-index of CFB was much higher than that of CA 19-9 (71.0 vs 50.4), suggesting that CFB outperforms CA 19-9 in discriminating PC from CP and other gastrointestinal cancers. This was further supported by immunoprecipitation and qRT-PCR assays showing higher expression of CFB in PC cell lines than in normal cell lines. A combination of CFB and CA 19-9 showed markedly improved sensitivity (90.1 vs 73.1%) over that of CFB alone in the diagnosis of PC against non-PC, with similar specificity (97.2 vs 97.9%). Thus, our results identify CFB as a novel serologic PC biomarker candidate and warrant further investigation into a large-scale validation and its role in molecular mechanism of pancreatic carcinogenesis.