title: Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma.
abstract: 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.
authors: Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
authors: Yuichi
authors: Y
authors: Nagao
authors: Masanori
authors: M
authors: Hisaoka
authors: Atsuji
authors: A
authors: Matsuyama
authors: Shuichi
authors: S
authors: Kanemitsu
authors: Tetsuo
authors: T
authors: Hamada
authors: Tokihiko
authors: T
authors: Fukuyama
authors: Ryuji
authors: R
authors: Nakano
authors: Akihiko
authors: A
authors: Uchiyama
authors: Masahiko
authors: M
authors: Kawamoto
authors: Koji
authors: K
authors: Yamaguchi
authors: Hiroshi
authors: H
authors: Hashimoto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000032:analysis*; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D007564:Japan; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000032:analysis*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D016601:RNA-Binding Proteins / Q000032:analysis*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis*; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3