TY - JOUR
T1 - MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3
AU - Selaru, Florin M.
AU - Olaru, Alexandru V.
AU - Kan, Takatsugu
AU - David, Stefan
AU - Cheng, Yulan
AU - Mori, Yuriko
AU - Yang, Jian
AU - Paun, Bogdan
AU - Jin, Zhe
AU - Agarwal, Rachana
AU - Hamilton, James P.
AU - Abraham, John
AU - Georgiades, Christos
AU - Alvarez, Hector
AU - Vivekanandan, Perumal
AU - Yu, Wayne
AU - Maitra, Anirban
AU - Torbenson, Michael
AU - Thuluvath, Paul J.
AU - Gores, Gregory J.
AU - LaRusso, Nicholas F.
AU - Hruban, Ralph
AU - Meltzer, Stephen J.
PY - 2009/5
Y1 - 2009/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=66149110971&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=66149110971&partnerID=8YFLogxK
U2 - 10.1002/hep.22838
DO - 10.1002/hep.22838
M3 - Article
C2 - 19296468
AN - SCOPUS:66149110971
SN - 0270-9139
VL - 49
SP - 1595
EP - 1601
JO - Hepatology
JF - Hepatology
IS - 5
ER -