Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Mod Pathol. 2012 Jan;25(1):112-21. doi: 10.1038/modpathol.2011.142. Epub 2011 Oct 7.
Since the discovery of small non-coding RNAs, the analyses of microRNA (miRNA) expression patterns in human cancer have provided new insights into cancer biology. miRNA-21 has been suggested to be one of the miRNAs that have an important role in the development or biological behavior of a variety of malignancies, including pancreatic cancer. This study was conducted to evaluate the relationship between the expression of miRNA-21 and that of its molecular targets, programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinase (TIMP3), in pancreatic ductal adenocarcinoma. The study included 65 pancreatic ductal adenocarcinomas and 5 normal pancreatic tissue specimens for comparison. The miRNA expression profiling of five selected pancreatic ductal adenocarcinomas and five normal pancreatic specimens was performed using a microarray platform, and was evaluated by a hierarchical clustering analysis. The miRNA most highly expressed in pancreatic ductal adenocarcinomas (ie, miRNA-21) was further assessed by quantitative real-time reverse transcription PCR (RT-PCR) assays in the 65 pancreatic ductal adenocarcinoma cases. The expression pattern of its molecular targets (eg, PDCD4 and TIMP3) in pancreatic ductal adenocarcinoma was examined immunohistochemically. In the microarray analyses, 28 miRNAs were upregulated in pancreatic ductal adenocarcinoma compared with normal pancreatic tissue, whereas 48 miRNAs were downregulated. miRNA-21 was the most significantly overexpressed miRNA in the pancreatic ductal adenocarcinomas analyzed, and was also highly expressed in 75% of the 65 pancreatic ductal adenocarcinomas examined by real-time RT-PCR. High miRNA-21 expression was correlated with a worse prognosis in the pancreatic ductal adenocarcinoma patients (P=0.045). The immunohistochemical expression patterns of PDCD4 (reduced nuclear staining pattern) and TIMP3 (downregulated expression) were significantly associated with both the upregulated miR-21 expression (P<0.05) and the poor survival of the patients (P<0.001 and P=0.001, respectively). Our data suggest that an overexpression of miRNA-21 is, therefore, associated with the biological behavior of pancreatic ductal adenocarcinoma via the downregulation of the expression of tumor suppressors, PDCD4 and TIMP3, thus resulting in tumor progression and the adverse clinical course of pancreatic ductal adenocarcinoma.
自小非编码 RNA 被发现以来，对人类癌症中 miRNA（miRNA）表达模式的分析为癌症生物学提供了新的见解。miRNA-21 已被认为是在多种恶性肿瘤（包括胰腺癌）的发展或生物学行为中具有重要作用的 miRNA 之一。本研究旨在评估 miRNA-21 与其分子靶标程序性细胞死亡因子 4（PDCD4）和组织金属蛋白酶抑制剂 3（TIMP3）在胰腺导管腺癌中的表达之间的关系。本研究纳入了 65 例胰腺导管腺癌和 5 例正常胰腺组织标本进行比较。使用微阵列平台对 5 例胰腺导管腺癌和 5 例正常胰腺标本进行 miRNA 表达谱分析，并通过层次聚类分析进行评估。在 65 例胰腺导管腺癌病例中，通过定量实时逆转录 PCR（RT-PCR）检测胰腺导管腺癌中表达最高的 miRNA（即 miRNA-21）。通过免疫组织化学检测其分子靶标（如 PDCD4 和 TIMP3）在胰腺导管腺癌中的表达模式。在微阵列分析中，与正常胰腺组织相比，胰腺导管腺癌中有 28 个 miRNA 上调，48 个 miRNA 下调。miRNA-21 是分析的胰腺导管腺癌中表达最显著上调的 miRNA，在 65 例胰腺导管腺癌中通过实时 RT-PCR 检测到其表达也高达 75%。miRNA-21 高表达与胰腺导管腺癌患者预后不良相关（P=0.045）。PDCD4（核染色模式减少）和 TIMP3（下调表达）的免疫组织化学表达模式与上调的 miR-21 表达（P<0.05）和患者的不良生存（P<0.001 和 P=0.001）显著相关。我们的数据表明，miRNA-21 的过度表达通过下调肿瘤抑制因子 PDCD4 和 TIMP3 的表达与胰腺导管腺癌的生物学行为相关，从而导致肿瘤进展和胰腺导管腺癌的不良临床病程。
