A microRNA prognostic signature for pancreatic ductal adenocarcinoma


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Nigel Jamieson2, Ross Carter1, Colin McKay1, Nicol Keith2, Karin Oien2

1West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, UK, 2University of Glasgow, UK

Abstract

Proffered paper presentation

Background
The dismal outcome associated with pancreatic ductal adenocarcinoma (PDAC) despite current therapy, demands the identification of accurate diagnostic as well as prognostic biomarkers. MicroRNAs (miRNAs) constitute a class of small (21-23 nucleotides) noncoding RNAs that function as post-transcriptional gene regulators with alteration in expression correlating with cancer pathogenesis. The aim of the current study was to investigate the miRNA expression profile associated with PDAC and to correlate this with patient outcome.

Method
We used 723 feature miRNA arrays (Agilent) to investigate miRNA expression in normal pancreas, PDAC tissues as well as PDAC-derived cell lines. Total RNA from tumour tissue from 42 PDAC patients undergoing pancreatico-duodenectomy with curative intent was profiled. The expression status of selected miRNAs was then investigated by real-time RT-PCR.

Results
MiRNA Microarray analysis identified unique profiles, which discriminate PDAC from non-cancerous pancreatic tissues included significant over expression of miR-155, miR-23a, miR-21 and let7i (p < 0.001) as well under-expression of miR-216a, miR-130b and miR-148a (p < 0.001). Molecular signatures that differ according to histopathological features and the presence of lymph node metastasis were also identified. Using a Cox proportional hazard regression model, expression of a number of miRNAs was found to correlate with outcome including miR30d, miR29c, miR224 and miR934 (p < 0.05), independent of tumour stage. Bioinformatic analysis of the predicted gene targets of the miRNAs of interest was performed to identify novel targets relevant to PDAC biology.

Conclusion
Our data provides novel insights into the miRNA-driven pathophysiological mechanisms involved in PDAC development offering new candidate targets to be exploited both for diagnostic and therapeutic strategies. Furthermore, following resection with curative intent, the miRNA molecular signature of PDAC correlates with patient survival.