EpCAM and α-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma
EpCAM and α-fetoprotein expression defines novel prognostic subtypes of hepatocellular carcinoma
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DOI：
10.1158/0008-5472.can-07-6013
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发表时间：
2008-03-01
期刊：
影响因子：
11.2
通讯作者：
Wang, Xin Wei
中科院分区：
文献类型：
--
作者：
Yamashita, Taro;Forgues, Marshorma;Wang, Xin Wei
肝细胞癌（HCC）的异质性和缺乏适当的生物标志物阻碍了患者的预后和治疗分层。最近，我们发现肝干细胞标志物上皮细胞粘附分子（EpCAM）可能作为 HCC 的早期生物标志物，因为它的表达在癌前肝组织和 HCC 的子集中高度升高。在这项研究中，我们旨在通过寻找 EpCAM 共表达基因来识别与肝谱系某些阶段相似的新型 HCC 亚型。通过对 40 个 HCC 病例的 cDNA 微阵列分析鉴定出 EpCAM 阳性 HCC 的独特特征，并通过对 238 个独立 HCC 病例的寡核苷酸微阵列分析进行验证，并通过对另外 101 个 HCC 病例的免疫组织化学分析进一步证实。 EpCAM 阳性 HCC 显示出具有肝祖细胞特征的独特分子特征，包括存在已知的干/祖细胞标记物，如细胞角蛋白 19、c-Kit、EpCAM 和激活的 Wnt-β-连环蛋白信号传导，而 EpCAM 阴性 HCC 显示具有成熟肝细胞特征的基因。此外，通过测定甲胎蛋白 (AFP) 水平，EpCAM 阳性和 EpCAM 阴性 HCC 可以进一步细分为具有预后意义的四组。这四种亚型表现出不同的基因表达模式，其特征类似于肝谱系的某些阶段。总之，我们提出了一个由 EpCAM 和 AFP 定义的简单分类系统，以揭示与肝细胞成熟谱系相似的 HCC 亚型，这可能有助于对接受辅助治疗的 HCC 患者进行预后分层和评估，并为 HCC 的潜在细胞起源及其激活的分子途径提供新的见解。
The heterogeneous nature of hepatocellular carcinoma (HCC) and the lack of appropriate biomarkers have hampered patient prognosis and treatment stratification. Recently, we have identified that a hepatic stem cell marker, epithelial cell adhesion molecule (EpCAM), may serve as an early biomarker of HCC because its expression is highly elevated in premalignant hepatic tissues and in a subset of HCC. In this study, we aimed to identify novel HCC subtypes that resemble certain stages of liver lineages by searching for EpCAM-coexpressed genes. A unique signature of EpCAM-positive HCCs was identified by cDNA microarray analysis of 40 HCC cases and validated by oligonucleotide microarray analysis of 238 independent HCC cases, which was further confirmed by immunohistochemical analysis of an additional 101 HCC cases. EpCAM-positive HCC displayed a distinct molecular signature with features of hepatic progenitor cells including the presence of known stem/progenitor markers such as cytokeratin 19, c-Kit, EpCAM, and activated Wnt-beta-catenin signaling, whereas EpCAM-negative HCC displayed genes with features of mature hepatocytes. Moreover, EpCAM-positive and EpCAM-negative HCC could be further subclassified into four groups with prognostic implication by determining the level of alpha-fetoprotein (AFP). These four subtypes displayed distinct gene expression patterns with features resembling certain stages of hepatic lineages. Taken together, we proposed an easy classification system defined by EpCAM and AFP to reveal HCC subtypes similar to hepatic cell maturation lineages, which may enable prognostic stratification and assessment of HCC patients with adjuvant therapy and provide new insights into the potential cellular origin of HCC and its activated molecular pathways.