Identification of MicroRNA-21 as a Biomarker for Chemoresistance and Clinical Outcome Following Adjuvant Therapy in Resectable Pancreatic Cancer

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The high risk of recurrence following surgical resection provides the rationale for adjuvant therapy. However, only a subset of patients benefit from adjuvant therapy. Identification of molecular markers to predict treatment outcome is therefore warranted. The aim of the present study was to evaluate whether expression of novel candidate biomarkers, including microRNAs, can predict clinical outcome in PDAC patients treated with adjuvant therapy.Methodology/Principal FindingsFormalin-fixed paraffin embedded specimens from a cohort of 82 resected Korean PDAC cases were analyzed for protein expression by immunohistochemistry and for microRNA expression using quantitative Real-Time PCR. Cox proportional hazards model analysis in the subgroup of patients treated with adjuvant therapy (N = 52) showed that lower than median miR-21 expression was associated with a significantly lower hazard ratio (HR) for death (HR = 0.316; 95%CI = 0.166–0.600; P = 0.0004) and recurrence (HR = 0.521; 95%CI = 0.280–0.967; P = 0.04). MiR-21 expression status emerged as the single most predictive biomarker for treatment outcome among all 27 biological and 9 clinicopathological factors evaluated. No significant association was detected in patients not treated with adjuvant therapy. In an independent validation cohort of 45 frozen PDAC tissues from Italian cases, all treated with adjuvant therapy, lower than median miR-21 expression was confirmed to be correlated with longer overall as well as disease-free survival. Furthermore, transfection with anti-miR-21 enhanced the chemosensitivity of PDAC cells.Conclusions SignificanceLow miR-21 expression was associated with benefit from adjuvant treatment in two independent cohorts of PDAC cases, and anti-miR-21 increased anticancer drug activity in vitro. These data provide evidence that miR-21 may allow stratification for adjuvant therapy, and represents a new potential target for therapy in PDAC.

MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma

“…MiR-21 was up-regulated in pancreatic adenocarcinomas in this and other studies and has been related to short survival. 20,22,38,39 Increased miR-21 expression increases the proliferative and invasive potential in several types of cancer, it has anti-apoptotic and pro-angiogenesis properties and its expression may represent an adaptation to a hypoxic environment that favors cancer cell survival. 40 In accordance with others, we found that miR-148a, miR-216b and miR-217b were some of the miRNAs with the most significantly decreased expression in pancreatic adenocarcinomas compared with chronic pancreatitis and normal pancreas.…”

miRNA-141, Downregulated in Pancreatic Cancer, Inhibits Cell Proliferation and Invasion by Directly Targeting MAP4K4

“…High priority must be given to understanding the mechanisms of occurrence and development of pancreatic cancer and identifying novel diagnostics and effective therapeutics (10,11). MiR-141 is a member of the miR-200 family that mainly affects the epithelial-mesenchymal transition (EMT) process (12)(13)(14)(15)(16)(17)(18).…”

Reduction of plasma MicroRNA-21 is associated with chemotherapeutic response in patients with non-small cell lung cancer

“…Yan et al [44] showed that overexpression of miR-21 was correlated with disease progression and poor prognosis in breast cancer. Recently, Hwang et al [45] investigated whether miR-21 can predict clinical outcome in pancreatic ductal adenocarcinoma (PDAC) patients treated with adjuvant therapy. The results suggested that low miR-21 expression was seen by adjuvant treatment in PDAC patients and anti-miR-21 increased anticancer drug activity in vitro.…”