MicroRNA Molecular Profiles Associated with Diagnosis, Clinicopathologic Criteria, and Overall Survival in Patients with Resectable Pancreatic Ductal Adenocarcinoma

Abstract

Purpose: MicroRNAs (miRNA) have potential as diagnostic and prognostic biomarkers and as therapeutic targets in cancer. We sought to establish the relationship between miRNA expression and clinicopathologic parameters, including prognosis, in pancreatic ductal adenocarcinoma (PDAC).Experimental Design: Global miRNA microarray expression profiling of prospectively collected freshfrozen PDAC tissue was done on an initial test cohort of 48 patients, who had undergone pancreaticoduodenectomy between 2003 and 2008 at a single institution. We evaluated association with tumor stage, lymph node status, and site of recurrence, in addition to overall survival, using Cox regression multivariate analysis. Validation of selected potentially prognostic miRNAs was done in a separate cohort of 24 patients.Results: miRNA profiling identified expression signatures associated with PDAC, lymph node involvement, high tumor grade, and 20 miRNAs were associated with overall survival. In the initial cohort of 48 PDAC patients, high expression of miR-21 (HR ¼ 3.22, 95% CI: 1.21-8.58) and reduced expression of miR34a (HR ¼ 0.15, 95% CI: 0.06-0.37) and miR-30d (HR ¼ 0.30, 95% CI: 0.12-0.79) were associated with poor overall survival following resection independent of clinical covariates. In a further validation set of 24 patients, miR-21 and miR-34a expression again significantly correlated with overall survival (P ¼ 0.031 and P ¼ 0.001).Conclusion: Expression patterns of miRNAs are significantly altered in PDAC. Aberrant expression of a number of miRNAs was independently associated with reduced survival, including overexpression of miR-21 and underexpression of miR-34a.Summary: miRNA expression profiles for resected PDAC were examined to identify potentially prognostic miRNAs. miRNA microarray analysis identified statistically unique profiles, which could discriminate PDAC from paired nonmalignant pancreatic tissues as well as molecular signatures that differ according to pathologic features. miRNA expression profiles correlated with overall survival of PDAC following resection, indicating that miRNAs provide prognostic utility.

Identifying Biomarkers and Drug Targets Using Systems Biology Approaches for Pancreatic Cancer

“…For example, miR-21 was increased, whereas miR-146a and let-7 families were decreased [30]. In line with this report, using miRNA microarray, 20 miRNAs were found to be associated with overall survival in PC [31]. Moreover, multiple miRNAs were correlated with lymph node metastasis and high tumor grade.…”

“…Moreover, multiple miRNAs were correlated with lymph node metastasis and high tumor grade. Specifically, up-regulation of miR-21 and down-regulation of miR-34a and miR-30d were associated with poor overall survival [31]. Similarly, a high-throughput miRNAs micorarray unravels the prognostic role of miR-211 in PC [32].…”

1p36 Tumor Suppression—A Matter of Dosage?

“…Aberrant miR-34a downregulation has been detected in many cancer types, including breast cancer (81), epithelial ovarian cancer (82), prostate carcinoma (80), pancreatic ductal adenocarcinoma (83), hepatocellular carcinoma (84), colon cancer (85), non-small cell lung cancer (86), neuroblastoma (87), glioblastoma (88), malignant peripheral nerve sheath tumors (89), melanoma (80), chronic lymphocytic leukemia (90)(91)(92), and acute myeloid leukemia (93). In many cancer entities, low miR-34a expression is associated with advanced disease and/or poor patient survival, as seen in neuroblastoma (87), epithelial ovarian cancer (82), peripheral nerve sheath tumors (89), breast cancer (81), and pancreatic ductal adenocarcinoma (83). Ectopic miR-34a expression induces cell cycle arrest, apoptosis, and senescence, and inhibits migration and invasion of cancer cells (94).…”

MiR-21 Upregulation Induced by Promoter Zone Histone Acetylation is Associated with Chemoresistance to Gemcitabine and Enhanced Malignancy of Pancreatic Cancer Cells

“…The expression of miR-21 has been shown to be involved in the progression of several types of cancers (Kwak et al, 2011;Yang et al, 2011), including PDAC (Bloomston et al, 2007;Szafranska et al, 2007;Nagao et al, 2012), and the up-regulation of miR-21 expression has been shown to correlate with a lower cancer survival rate (Dillhoff et al, 2008;Jamieson et al, 2012). Recent studies also demonstrated that miR-21 modulates the chemosensitivity of cancer cells primarily by targeting PTEN or PDCD4 (Moriyama et al, 2009;Ali et al, 2010;Giovannetti et al, 2010;Tomimaru et al, 2010).…”