Institute of Pathology, Ruhr-University Bochum, Bochum, Germany.
Int J Cancer. 2012 Jul 15;131(2):E86-95. doi: 10.1002/ijc.26466. Epub 2011 Nov 19.
Pancreatic ductal adenocarcinoma (PDAC) is known for its poor prognosis resulting from being diagnosed at an advanced stage. Accurate early diagnosis and new therapeutic modalities are therefore urgently needed. MicroRNAs (miRNAs), considered a new class of biomarkers and therapeutic targets, may be able to fulfill those needs. Combining tissue microdissection with global miRNA array analyses, cell type-specific miRNA expression profiles were generated for normal pancreatic ductal cells, acinar cells, PDAC cells derived from xenografts and also from macrodissected chronic pancreatitis (CP) tissues. We identified 78 miRNAs differentially expressed between ND and PDAC cells providing new insights into the miRNA-driven pathophysiological mechanisms involved in PDAC development. Having filtered miRNAs which are upregulated in the three pairwise comparisons of PDAC vs. ND, PDAC vs. AZ and PDAC vs. CP, we identified 15 miRNA biomarker candidates including miR-135b. Using relative qRT-PCR to measure miR-135b normalized to miR-24 in 75 FFPE specimens (42 PDAC and 33 CP) covering a broad range of tumor content, we discriminated CP from PDAC with a sensitivity and specificity of 92.9% [95% CI=(80.5, 98.5)] and 93.4% [95% CI=(79.8, 99.3)], respectively. Furthermore, the area under the curve (AUC) value reached of 0.97 was accompanied by positive and negative predictive values of 95% and 91%, respectively. In conclusion, we report pancreatic cell-specific global miRNA profiles, which offer new candidate miRNAs to be exploited for functional studies in PDAC. Furthermore, we provide evidence that miRNAs are well-suited analytes for development of sensitive and specific aid-in-diagnosis tests for PDAC.
胰腺导管腺癌 (PDAC) 以其在晚期诊断的不良预后而闻名。因此，迫切需要准确的早期诊断和新的治疗方法。微小 RNA (miRNA) 被认为是一类新的生物标志物和治疗靶点，可能能够满足这些需求。通过组织微切割与全局 miRNA 阵列分析相结合，生成了正常胰腺导管细胞、腺泡细胞、异种移植衍生的 PDAC 细胞以及宏观切割的慢性胰腺炎 (CP) 组织的细胞特异性 miRNA 表达谱。我们鉴定了 78 个在 ND 和 PDAC 细胞之间差异表达的 miRNA，为 miRNA 驱动的 PDAC 发展相关病理生理机制提供了新的见解。在 PDAC 与 ND、PDAC 与 AZ 和 PDAC 与 CP 的三个两两比较中，筛选上调的 miRNA 后，我们鉴定了 15 个 miRNA 生物标志物候选物，包括 miR-135b。使用相对 qRT-PCR 测量 75 个 FFPE 标本（42 个 PDAC 和 33 个 CP）中 miR-135b 相对于 miR-24 的归一化值，该标本涵盖了广泛的肿瘤含量，我们以 92.9%[95%CI=(80.5,98.5)]的灵敏度和 93.4%[95%CI=(79.8,99.3)]的特异性区分 CP 和 PDAC。此外，曲线下面积 (AUC) 值达到 0.97，阳性预测值和阴性预测值分别为 95%和 91%。总之，我们报告了胰腺细胞特异性的全局 miRNA 谱，为 PDAC 的功能研究提供了新的候选 miRNA。此外，我们提供的证据表明，miRNA 非常适合开发用于 PDAC 的敏感和特异性辅助诊断测试的分析物。
