National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Hepatology. 2012 Nov;56(5):1792-803. doi: 10.1002/hep.25890. Epub 2012 Aug 22.
Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its tumor heterogeneity and molecular characteristics are largely unknown. In this study, we conducted transcriptomic profiling of 23 ICC and combined hepatocellular cholangiocarcinoma tumor specimens from Asian patients using Affymetrix messenger RNA (mRNA) and NanoString microRNA microarrays to search for unique gene signatures linked to tumor subtypes and patient prognosis. We validated the signatures in an additional 68 ICC cases derived from Caucasian patients. We found that both mRNA and microRNA expression profiles could independently classify Asian ICC cases into two main subgroups, one of which shared gene expression signatures with previously identified hepatocellular carcinoma (HCC) with stem cell gene expression traits. ICC-specific gene signatures could predict survival in Asian HCC cases and independently in Caucasian ICC cases. Integrative analyses of the ICC-specific mRNA and microRNA expression profiles revealed that a common signaling pathway linking miR-200c signaling to epithelial-mesenchymal transition (EMT) was preferentially activated in ICC with stem cell gene expression traits. Inactivation of miR-200c resulted in an induction of EMT, whereas activation of miR-200c led to a reduction of EMT including a reduced cell migration and invasion in ICC cells. We also found that miR-200c and neural cell adhesion molecule 1 (NCAM1) expression were negatively correlated and their expression levels were predictive of survival in ICC samples. NCAM1, a known hepatic stem/progenitor cell marker, was experimentally demonstrated to be a direct target of miR-200c.
Our results indicate that ICC and HCC share common stem-like molecular characteristics and poor prognosis. We suggest that the specific components of EMT may be exploited as critical biomarkers and clinically relevant therapeutic targets for an aggressive form of stem cell-like ICC.
肝内胆管细胞癌（ICC）是原发性肝癌的第二大常见类型。然而，其肿瘤异质性和分子特征在很大程度上尚不清楚。在这项研究中，我们对来自亚洲患者的 23 例 ICC 和合并肝细胞胆管细胞癌肿瘤标本进行了转录组谱分析，使用 Affymetrix 信使 RNA（mRNA）和 NanoString 微 RNA 微阵列来寻找与肿瘤亚型和患者预后相关的独特基因特征。我们在另外 68 例来自白种人的 ICC 病例中验证了这些特征。我们发现，mRNA 和微 RNA 表达谱都可以独立地将亚洲 ICC 病例分为两个主要亚组，其中一个亚组与先前确定的具有干细胞基因表达特征的肝细胞癌（HCC）具有相似的基因表达特征。ICC 特异性基因特征可以预测亚洲 HCC 病例的生存情况，在白种人 ICC 病例中也可以独立预测。对 ICC 特异性 mRNA 和微 RNA 表达谱的综合分析表明，一条将 miR-200c 信号与上皮间质转化（EMT）联系起来的共同信号通路在具有干细胞基因表达特征的 ICC 中优先激活。miR-200c 的失活导致 EMT 的诱导，而 miR-200c 的激活导致 EMT 的减少，包括 ICC 细胞迁移和侵袭的减少。我们还发现，miR-200c 和神经细胞黏附分子 1（NCAM1）的表达呈负相关，它们的表达水平可预测 ICC 样本的生存情况。NCAM1 是已知的肝干细胞/祖细胞标志物，实验证明其是 miR-200c 的直接靶标。
我们的结果表明，ICC 和 HCC 具有共同的类干细胞分子特征和不良预后。我们建议 EMT 的特定成分可能被用作侵袭性类干细胞 ICC 的关键生物标志物和临床相关的治疗靶点。
