MICRORNA MIR-155 IS A BIOMARKER OF EARLY PANCREATIC NEOPLASIA

Abstract

Background: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions of pancreatic cancer. Misexpression of microRNAs (miRNAs) has emerged as a common feature of most human cancers, including pancreatic adenocarcinoma. In contrast, miRNA abnormalities in pancreatic cancer precursor lesions have not been systematically documented. Experimental Design: Relative expression levels of a panel of twelve miRNAs upregulated in pancreatic cancers were assessed in 15 microdissected non-invasive IPMNs versus matched normal pancreata, using quantitative reverse transcription PCR (qRT-PCR). Two significantly overexpressed miRNAs - miR-155 and miR-21 - were evaluated by locked nucleic acid in situ hybridization (LNA-ISH) in a panel of 64 archival IPMNs of all histological grades. The expression of miR-155 and miR-21 was also evaluated by qRT-PCR in pancreatic juice samples obtained from 10 patients with surgically resected IPMNs and five patients with non-neoplastic pancreato-biliary disorders ("disease controls"). Results: Significant overexpression by qRT-PCR of ten of the twelve miRNAs was observed in the 15 IPMNs versus matched controls (P < 0.05), with miR-155 (mean 11.6-fold) and miR-21 (mean 12.1-fold) demonstrating highest relative fold-changes in the precursor lesions. LNA-ISH confirmed the expression of miR-155 in 53 of 64 (83%) IPMNs compared to 4 of 54 (7%) normal ducts, and of miR-21 in 52 of 64 (81%) IPMNs compared to 1 of 54 (2%) normal ducts, respectively (P < 0.0001). A significantly higher proportion of IPMNs with carcinoma-in-situ expressed either miR-155 or miR-21, relative to IPMN adenomas (P < 0.01); in addition, miR-155 expression was demonstrable with significantly greater frequency in intestinal-type IPMNs (19 of 19, 100%) versus IPMNs with gastric foveolar-type lining (4 of 7, 57%) (P = 0.01). Upregulation of miR-155 transcripts by qRT-PCR was observed in 6 of 10 (60%) IPMN-associated pancreatic juice samples compared to 0 of 5 (0%) disease controls. Conclusions: Aberrant miRNA expression is an early event in the multistage progression of pancreatic cancer. Based on our results, miR-155 warrants further evaluation as a biomarker for IPMNs in clinical samples.