MicroRNA-21 is overexpressed in human cholangiocarcinoma... : Hepatology (original) (raw)

Hepatobiliary Malignancies

MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3#

Selaru, Florin M.1*† ‡; Olaru, Alexandru V.1†; Kan, Takatsugu1†; David, Stefan1; Cheng, Yulan1; Mori, Yuriko1; Yang, Jian1; Paun, Bogdan1; Jin, Zhe1; Agarwal, Rachana1; Hamilton, James P.1; Abraham, John1; Georgiades, Christos2; Alvarez, Hector3; Vivekanandan, Perumal3; Yu, Wayne4; Maitra, Anirban3,4; Torbenson, Michael3; Thuluvath, Paul J.1; Gores, Gregory J.5; LaRusso, Nicholas F.5; Hruban, Ralph3; Meltzer, Stephen J.1

1 Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University, Baltimore, MD

2 Department of Radiology, Johns Hopkins University, Baltimore, MD

3 Division of Pathology, Johns Hopkins University, Baltimore, MD

4 Division of Oncology, Johns Hopkins University, Baltimore, MD

5 Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN

* Division of Gastroenteroloy and Hepatology, Johns Hopkins University, 1503 E. Jefferson St., Room 106, Baltimore, MD, 21287

Email:[email protected]

Received September 2, 2008; accepted January 6, 2009.

Published online 18 March 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: National Institutes of Health (NIH); Grant Numbers: CA85069 CA85069 CA77057 CA106763 T32DK07632; Grant sponsor: 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.

# Potential conflict of interest: Nothing to report.

† These authors contributed equally to this work.

‡ fax: (410) 502-1329

Additional Supporting Information may be found in the online version of this article.

Abstract

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.)