Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer

• Published in: PloS one Vol. 5; no. 5; p. e10630
• Main Authors: Hwang, Jin-Hyeok, Voortman, Johannes, Giovannetti, Elisa, Steinberg, Seth M, Leon, Leticia G, Kim, Yong-Tae, Funel, Niccola, Park, Joo Kyung, Kim, Min A, Kang, Gyeong Hoon, Kim, Sun-Whe, Del Chiaro, Marco, Peters, Godefridus J, Giaccone, Giuseppe
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.05.2010; Public Library of Science (PLoS)
• Subjects: Adenocarcinoma; Adjuvant chemotherapy; Adjuvant therapy; Aged; Anticancer properties; Apoptosis; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Cancer therapies; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - surgery; Care and treatment; Cell Proliferation - drug effects; Cell survival; Chemokines; Chemoresistance; Chemotherapy; Chemotherapy, Adjuvant; Clinical outcomes; Cohort Studies; Cytotoxicity; Disease-Free Survival; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Fluorouracil - pharmacology; Gastroenterology and Hepatology/Gastrointestinal Cancers; Gastroenterology and Hepatology/Pancreas; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Genetics and Genomics/Cancer Genetics; Hazards; Hospitals; Humans; Immunohistochemistry; Internal medicine; Italy; Korea; Male; Medical prognosis; Medical research; Medicine; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; miRNA; Molecular Biology; Mortality; Multivariate Analysis; Mutation; Oligonucleotide Array Sequence Analysis; Oncology; Oncology/Gastrointestinal Cancers; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - surgery; Paraffin; Pathology; Patient outcomes; Patients; Prognosis; Proportional Hazards Models; Proteins; Recurrence; Reproducibility of Results; Ribonucleic acid; RNA; Statistical models; Stem cells; Surgery; Therapy; Tissues; Transfection; Treatment Outcome; Tumors; Vascular endothelial growth factor; Italy; Korea; United States > US; Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0010630

Pancreatic 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. Formalin-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. Low 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.