Selaru Florin M, Olaru Alexandru V, Kan Takatsugu, David Stefan, Cheng Yulan, Mori Yuriko, Yang Jian, Paun Bogdan, Jin Zhe, Agarwal Rachana, Hamilton James P, Abraham John, Georgiades Christos, Alvarez Hector, Vivekanandan Perumal, Yu Wayne, Maitra Anirban, Torbenson Michael, Thuluvath Paul J, Gores Gregory J, LaRusso Nicholas F, Hruban Ralph, Meltzer Stephen J
Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
Hepatology. 2009 May;49(5):1595-601. doi: 10.1002/hep.22838.
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.
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.
胆管癌（CCA）是侵袭性癌症，死亡率高且生存率低。只有根治性手术能给患者带来一些治愈的希望；然而，由于诊断手段准确性相对较差导致诊断较晚，大多数患者不适合手术。微小RNA（miR）参与了所有已检测的癌症，但尚未在原发性CCA中进行评估。在本研究中，对5个原发性CCA和5个正常胆管标本（NBD）进行了miR阵列分析。有几种miR表达失调，且miR-21在CCA中过表达。通过定量逆转录聚合酶链反应（qRT-PCR）验证了这10个标本中miR-21的差异表达。为了验证这些发现，随后对另外18个原发性CCA和12个正常肝脏标本进行了miR-21的qRT-PCR检测。MiR-21在区分CCA和正常组织时的敏感性为95%，特异性为100%，受试者操作特征曲线下面积为0.995。miR-21抑制剂可增加程序性细胞死亡4（PDCD4）和金属蛋白酶组织抑制剂3（TIMP3）的蛋白水平。值得注意的是，CCA中TIMP3的信使RNA水平明显低于正常组织。
MiR-21在人类CCA中过表达。此外，miR-21可能至少部分通过抑制PDCD4和TIMP3而具有致癌性。最后，这些数据表明TIMP3是胆管树中的一个候选肿瘤抑制基因。
