Huang Tianhe, Jiang Shi-Wen, Qin Liangyi, Senkowski Christopher, Lyle Christian, Terry Karen, Brower Steven, Chen Haibin, Glasgow Wayne, Wei Yongchang, Li Jinping
Department of Clinical Oncology, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA.
Int J Mol Sci. 2015 Jan 29;16(2):2956-70. doi: 10.3390/ijms16022956.
Human epididymis protein 4 (HE4) is a recognized biomarker in ovarian and endometrial cancer and over-expressed in pancreatic adenocarcinoma. The diagnostic value of HE4 in pancreatic adenocarcinoma remains unknown. Here we elucidate mRNA, protein and serum level of HE4 in pancreatic adenocarcinoma. HE4 mRNA level in tumor adjacent tissues and pancreatic adenocarcinoma tissues were tested by real time-PCR. Tissue microarray containing normal, adenocarcinoma, and adjacent pancreatic tissue was tested by immunohistochemistry (IHC). Serum level of HE4, carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 15-3 (CA15-3) and carbohydrate antigen 125 (CA125) were detected by ELISA assay in control and tumor patients. Further we compared the sensitivity and specificity of determining HE4, CA19-9, CA15-3, and CA125 for diagnosis of pancreatic adenocarcinoma and assessed the complementary diagnostic value of HE4, CA19-9, CA15-3 and CA125. Real time PCR showed significantly increased HE4 mRNA level in pancreatic adenocarcinoma compared with control. Result of IHC showed that HE4 significantly higher expressed in the human pancreatic carcinoma tissues than in both normal and adjacent non-tumorous pancreatic tissues, and the staining intensity is inversely correlated with the clinical stage. HE4 was highly expressed in early stage of pancreatic adenocarcinoma. Serum HE4 level is higher in cases with pancreatic adenocarcinoma than in the controls. Serum HE4 levels could research to a sensitivity of 45.83% and specificity of 93.75% when the Cutoff was set at 4.59 ng/mL. The Combined HE4 and CA19-9 increased the sensitivity to 83.33%; and interestingly, the combination of HE4 with CA15-3 led to the most powerful sensitivity of 87.5%. Combined with CA19-9 and CA15-3, HE4 could be a potential biomarker to improve the diagnostic power for pancreatic adenocarcinoma.
人附睾蛋白4（HE4）是卵巢癌和子宫内膜癌中公认的生物标志物，在胰腺腺癌中过表达。HE4在胰腺腺癌中的诊断价值尚不清楚。在此，我们阐明了胰腺腺癌中HE4的mRNA、蛋白和血清水平。通过实时聚合酶链反应检测肿瘤邻近组织和胰腺腺癌组织中的HE4 mRNA水平。采用免疫组织化学（IHC）检测包含正常、腺癌和胰腺邻近组织的组织芯片。通过酶联免疫吸附测定法检测对照患者和肿瘤患者血清中HE4、糖类抗原19-9（CA19-9）、糖类抗原15-3（CA15-3）和糖类抗原125（CA125）的水平。此外，我们比较了HE4、CA19-9、CA15-3和CA125对胰腺腺癌诊断的敏感性和特异性，并评估了HE4、CA19-9、CA15-3和CA125的联合诊断价值。实时聚合酶链反应显示，与对照组相比，胰腺腺癌中HE4 mRNA水平显著升高。免疫组织化学结果显示，HE4在人胰腺癌组织中的表达明显高于正常和邻近的非肿瘤胰腺组织，且染色强度与临床分期呈负相关。HE4在胰腺腺癌早期高表达。胰腺腺癌患者血清HE4水平高于对照组。当临界值设定为4.59 ng/mL时，血清HE4水平检测的敏感性为45.83%，特异性为93.75%。HE4与CA19-9联合使用可将敏感性提高至83.33%；有趣的是，HE4与CA15-3联合使用时敏感性最强，达到87.5%。与CA19-9和CA15-3联合使用时，HE4可能是提高胰腺腺癌诊断效能的潜在生物标志物。
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