State Key Laboratory of Molecular Oncology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Carcinogenesis. 2013 Mar;34(3):595-604. doi: 10.1093/carcin/bgs372. Epub 2012 Nov 27.
To date, the useful markers of hepatocellular carcinoma (HCC) remains incompletely developed. Here, we show that annexin A2 complement alpha-fetoprotein (AFP), a widely used liver cancer marker, in the serologically surveillance and early detection of HCC. First, differentially expressed proteins in HCC were identified using a subcellular proteomic approach. Annexin A2 was then selected for further verification. It was found to be overexpressed in HCC tissues (60.7%, 136/224). Using a self-established sandwich enzyme-linked immunosorbent assay, we found that annexin A2 significantly increased in the sera of HCC (n = 175, median, 24.75 ng/µl) compared with the healthy (n = 49, median, 16.69 ng/µl), benign tumors (n = 19, median, 19.92 ng/µl), hepatitis (n = 23, median, 6.48 ng/µl) and cirrhosis (n = 51, median, 7.39 ng/µl) controls and other malignant tumors (n = 87). Importantly, raised concentrations of annexin A2 were observed in 83.2% (79/95) of early stage (median, 24.32 ng/µl) and 78.4% (58/74) of AFP-negative (median, 24.09 ng/µl) patients. Annexin A2 alone had a better area under the receiver-operating characteristic curve (AUC = 0.79, 95% confidence interval: 0.73-0.85) in comparison with AFP (AUC = 0.73, 95% confidence interval: 0.66-0.80) in detecting of early stage HCC. Combining both markers notably improved the diagnostic efficiency of early HCC with an achieved sensitivity of 87.4%. Additionally, the expression characteristics of annexin A2 during hepatocarcinogenesis were detected in p21-HBx gene knockin transgenic mice model. The results showed that annexin A2 expression was substantially elevated in HCC-bearing mice, in accordance with the finding in human samples. In conclusion, annexin A2 may be an independent serological candidate for hepatitis B virus-related HCC, especially in the early stage cases with normal serum AFP.
迄今为止，肝细胞癌 (HCC) 的有用标志物仍未完全开发。在这里，我们表明， annexin A2 补体 alpha-胎蛋白 (AFP)，一种广泛使用的肝癌标志物，在 HCC 的血清学监测和早期检测中具有补充作用。首先，我们使用亚细胞蛋白质组学方法鉴定 HCC 中的差异表达蛋白。然后选择 annexin A2 进行进一步验证。发现它在 HCC 组织中过度表达（60.7%，136/224）。使用自行建立的夹心酶联免疫吸附试验，我们发现 annexin A2 在 HCC 患者的血清中显著增加（n=175，中位数，24.75ng/µl），与健康对照组（n=49，中位数，16.69ng/µl）、良性肿瘤组（n=19，中位数，19.92ng/µl）、肝炎组（n=23，中位数，6.48ng/µl）和肝硬化组（n=51，中位数，7.39ng/µl）以及其他恶性肿瘤组（n=87）相比。重要的是，在 83.2%（79/95）的早期（中位数，24.32ng/µl）和 78.4%（58/74）的 AFP 阴性（中位数，24.09ng/µl）患者中观察到 annexin A2 的浓度升高。与 AFP（AUC=0.73，95%置信区间：0.66-0.80）相比， annexin A2 单独检测早期 HCC 的曲线下面积（AUC）更好（AUC=0.79，95%置信区间：0.73-0.85）。同时检测两种标志物可显著提高早期 HCC 的诊断效率，达到 87.4%的敏感性。此外，在 p21-HBx 基因敲入转基因小鼠模型中检测到 annexin A2 在肝癌发生过程中的表达特征。结果表明，在携带 HCC 的小鼠中 annexin A2 的表达显著升高，与人类样本的结果一致。总之， annexin A2 可能是乙型肝炎病毒相关 HCC 的独立血清学候选标志物，特别是在 AFP 正常的早期病例中。
