MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3
✍ Scribed by 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. Gores; Nicholas F. LaRusso; Ralph Hruban; Stephen J. Meltzer
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 547 KB
- Volume
- 49
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
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;49:1595-1601.) C holangiocarcinoma, an epithelial cancer of the biliary tree, 1 is the second most common primary hepatic malignancy, 2 with a United States incidence of 0.82-0.95/100,000. 3 Although the rate of extrahepatic CCA has remained stable, intrahepatic CCA has increased by more than 100% in the past 40 years. 4 Survival in CCA is dismal, usually measured in months. 5 The only potentially curative treatment for CCA is surgical resection. 6 Unfortunately, the vast majority of patients are diagnosed at late stages, when surgery is not a viable option. 7,8 This late diagnosis stems from a paucity of diseasespecific symptoms in early stages. 2 Moreover, in earlier stages of CCA, diagnostic techniques are plagued by low specificity. 2 These considerations demand a better understanding of cholangiocarcinogenesis, with an emphasis on biomarkers for earlier diagnosis.
MicroRNAs (miRs) are noncoding RNAs 18 to 25 nucleotides in length. 9 The effects of miRs are mediated by binding to target messenger (m)RNAs and either suppressing translation or degrading miR-bound mRNA. 10 Groundbreaking research in CCA cell lines has revealed important miR differences among CCA and normal