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

Florin M. Selaru, Alexandru V. Olaru, Takatsugu Kan, Stefan David, Yulan Cheng, Yuriko Mori, Jian Yang, Bogdan Paun, Zhe Jin, Rachana Agarwal, James P. Hamilton, John Abraham, Christos Georgiades, Hector Alvarez, Perumal Vivekanandan, Wayne Yu, Anirban Maitra, Michael Torbenson, Paul J. Thuluvath, Gregory J. GoresNicholas F. LaRusso, Ralph Hruban, Stephen J. Meltzer

Research output: Contribution to journalArticle

208 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1595-1601
Number of pages7
JournalHepatology
Volume49
Issue number5
DOIs
StatePublished - May 1 2009

    Fingerprint

ASJC Scopus subject areas

  • Hepatology

Cite this

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., ... 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(5), 1595-1601. https://doi.org/10.1002/hep.22838