These authors contributed equally to this work.
MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3†
Article first published online: 4 FEB 2009
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 49, Issue 5, pages 1595–1601, May 2009
How to Cite
Selaru, F. M., Olaru, A. V., Kan, T., David, S., Cheng, Y., Mori, Y., Yang, J., Paun, B., Jin, Z., Agarwal, R., Hamilton, J. P., Abraham, J., Georgiades, C., Alvarez, H., Vivekanandan, P., Yu, W., Maitra, A., Torbenson, M., Thuluvath, P. J., Gores, G. J., LaRusso, N. F., Hruban, R. and Meltzer, S. J. (2009), MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3. Hepatology, 49: 1595–1601. doi: 10.1002/hep.22838
Potential conflict of interest: Nothing to report.
- Issue published online: 27 APR 2009
- Article first published online: 4 FEB 2009
- Accepted manuscript online: 4 FEB 2009 12:00AM EST
- Manuscript Accepted: 6 JAN 2009
- Manuscript Received: 2 SEP 2008
- National Institutes of Health (NIH). Grant Numbers: CA85069, CA85069, CA77057, CA106763, T32DK07632
- American Gastroenterological Association/Foundation for Digestive Health and Nutrition Fellowship to Faculty Transition Award and Flight Attendant Medical Research Institute's Young Clinical Scientist Award
Cholangiocarcinomas (CCAs) are aggressive cancers, with high mortality and poor survival rates. Only radical surgery offers patients some hope of cure; however, most patients are not surgical candidates because of late diagnosis secondary to relatively poor accuracy of diagnostic means. MicroRNAs (miRs) are involved in every cancer examined, but they have not been evaluated in primary CCA. In this study, miR arrays were performed on five primary CCAs and five normal bile duct specimens (NBDs). Several miRs were dysregulated and miR-21 was overexpressed in CCAs. miR-21 differential expression in these 10 specimens was verified by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). To validate these findings, qRT-PCR for miR-21 was then performed on 18 additional primary CCAs and 12 normal liver specimens. MiR-21 was 95% sensitive and 100% specific in distinguishing between CCA and normal tissues, with an area under the receiver operating characteristic curve of 0.995. Inhibitors of miR-21 increased protein levels of programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinases 3 (TIMP3). Notably, messenger RNA levels of TIMP3 were significantly lower in CCAs than in normals. Conclusions: MiR-21 is overexpressed in human CCAs. Furthermore, miR-21 may be oncogenic, at least in part, by inhibiting PDCD4 and TIMP3. Finally, these data suggest that TIMP3 is a candidate tumor suppressor gene in the biliary tree. (HEPATOLOGY 2009.)