MicroRNA-21 Is Induced Early in Pancreatic Ductal Adenocarcinoma Precursor Lesions

• Published in: Clinical chemistry (Baltimore, Md.) Vol. 56; no. 4; pp. 603 - 612
• Main Authors: du Rieu, Mael Chalret, Torrisani, Jerome, Selves, Janick, Al Saati, Talal, Souque, Anny, Dufresne, Marlene, Tsongalis, Gregory J, Suriawinata, Arief A, Carrere, Nicolas, Buscail, Louis, Cordelier, Pierre
• Format: Journal Article
• Language: English
• Published: Washington, DC Am Assoc Clin Chem 01.04.2010; American Association for Clinical Chemistry; Oxford University Press
• Subjects: Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adenocarcinoma - surgery; Analytical, structural and metabolic biochemistry; Animals; Biological and medical sciences; Biomarkers, Tumor - genetics; Cancer; Cancer therapies; Carcinoma, Pancreatic Ductal; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Carcinoma, Pancreatic Ductal - surgery; Cell Line, Tumor; Disease Models, Animal; Ethics; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression Profiling; Human subjects; Humans; In Situ Hybridization, Fluorescence; Investigative techniques, diagnostic techniques (general aspects); Kinases; Lesions; Life Sciences; Medical sciences; Mice; Mice, Knockout; MicroRNAs; MicroRNAs - genetics; Molecular biophysics; Mortality; Pancreatic Neoplasms; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - surgery; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Sarcoma; Sensitivity and Specificity; Survival; Tumor Markers, Biological; RNA interference; Micro RNA; Pancreas ductal adenocarcinoma; Biochemistry; Malignant tumor; Precursor; Gene silencing; Clinical biology; Pancreas cancer; Digestive diseases; Early; Lesion; Molecular biology; Cancer; Pancreatic disease
• ISSN: 0009-9147; 1530-8561; 1530-8561
• DOI: 10.1373/clinchem.2009.137364

Background: Pancreatic ductal adenocarcinoma (PDAC) has the poorest overall prognosis among gastrointestinal cancers; however, curative resection in early-stage PDAC greatly improves survival rates, indicating the importance of early detection. Because abnormal microRNA production is commonly detected in cancer, we investigated noninvasive precursor pancreatic intraepithelial neoplasia (PanIN) lesions for microRNA production as a potential early biomarker of PDAC. Methods: Pathologists identified and classified ductal lesions. We extracted total RNA from laser-capture microdissected PanIN tissue samples from a conditional KRAS(G12D) mouse model (n = 29) or of human origin (n = 38) (KRAS is v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). MicroRNA production was quantified by quantitative real-time PCR. Internal controls included 5S and U6 RNAs. Results: Production of microRNAs miR-21, miR-205, and miR-200 paralleled PanIN progression in the KRAS(G12D) mouse model, compared with microRNA production in samples of nonpathologic ducts. miR-21 demonstrated the highest relative concentrations in the precursor lesions. Interestingly, miR-205 and miR-21 up-regulation preceded phenotypic changes in the ducts. The production of microRNAs miR-21, miR-221, miR-222, and let-7a increased with human PanIN grade, with peak production occurring in hyperplastic PanIN-2/3 lesions. In situ hybridization analysis indicated miR-21 production to be concentrated in pathologic ductal cells. miR-21 production was regulated by KRAS(G12D) and epidermal growth factor receptor in PDAC-derived cell lines. Conclusions: Aberrant microRNA production is an early event in the development of PanIN. Our findings indicate that miR-21 warrants further investigation as a marker for early detection of PDAC.