Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea.
Hepatology. 2011 Nov;54(5):1707-17. doi: 10.1002/hep.24559.
There is a recently proposed subtype of hepatocellular carcinoma (HCC) that is histologically similar to usual HCC, but characterized by the expression of "stemness"-related markers. A large-scale study on two different cohorts of HCCs was performed to investigate the clinicopathologic features and epithelial-mesenchymal transition (EMT)-related protein expression status of this subtype of HCCs. The expression status of stemness-related (e.g., keratin 19 [K19], cluster of differentiation [CD]133, epithelial cell adhesion molecule [EpCAM], and c-kit) and EMT-related markers (e.g., snail, S100A4, urokinase plasminogen activator receptor [uPAR], ezrin, vimentin, E-cadherin, and matrix metalloproteinase [MMP]2) were examined using tissue microarrays from cohort 1 HCCs (n = 137). K19 protein expression in cohort 2 HCCs (n = 237) was correlated with the clinicopathologic parameters and messenger RNA (mRNA) levels of K19, uPAR, VIL2, Snail, Slug, and Twist. K19, EpCAM, c-kit, and CD133 positivity were observed in 18.2%, 35.0%, 34.3%, and 24.8%, respectively. K19 was most frequently expressed in combination with at least one other stemness-related marker (92.0%). K19-positive HCCs demonstrated more frequent major vessel invasion and increased tumor size, compared to K19-negative HCCs (P < 0.05). K19 was most significantly associated with EMT-related protein expression (e.g., vimentin, S100A4, uPAR, and ezrin) (P < 0.05) and a poor prognosis (overall survival: P = 0.018; disease-free survival: P = 0.007) in cohort 1. In cohort 2, HCCs with high K19 mRNA levels demonstrated higher mRNA levels of Snail, uPAR, and MMP2 (P < 0.05). K19-positive HCCs demonstrated more frequent microvascular invasion, fibrous stroma, and less tumor-capsule formation, compared to K19-negative HCCs (P < 0.05). K19 expression was a significant independent predictive factor of poor disease-free survival (P = 0.032).
K19 was well correlated with clinicopathologic features of tumor aggressiveness, compared to other stemness-related proteins. K19-positive HCCs showed significantly increased EMT-related protein and mRNA expression, suggesting that they may acquire more invasive characteristics, compared to K19-negative HCCs through the up-regulation of EMT-associated genes.
最近提出了一种肝细胞癌（HCC）的亚型，其组织学上与普通 HCC 相似，但以“干性”相关标志物的表达为特征。对来自 HCC 的两个不同队列进行了大规模研究，以研究该 HCC 亚型的临床病理特征和上皮-间充质转化（EMT）相关蛋白表达状态。使用来自队列 1 HCC（n=137）的组织微阵列检查了干性相关标志物（例如角蛋白 19 [K19]、分化簇 [CD]133、上皮细胞黏附分子 [EpCAM]和 c-kit）和 EMT 相关标志物（例如 snail、S100A4、尿激酶纤溶酶原激活物受体[uPAR]、ezrin、波形蛋白、E-钙黏蛋白和基质金属蛋白酶 [MMP]2）的表达状态。队列 2 HCC（n=237）的 K19 蛋白表达与临床病理参数和 K19、uPAR、VIL2、Snail、Slug 和 Twist 的信使 RNA（mRNA）水平相关。K19、EpCAM、c-kit 和 CD133 的阳性率分别为 18.2%、35.0%、34.3%和 24.8%。K19 阳性 HCC 与至少一种其他干性相关标志物的组合表达最为频繁（92.0%）。K19 阳性 HCC 与 K19 阴性 HCC 相比，更常发生主要血管侵犯和肿瘤增大（P<0.05）。在队列 1 中，K19 与 EMT 相关蛋白表达（例如波形蛋白、S100A4、uPAR 和 ezrin）（P<0.05）和不良预后（总生存：P=0.018；无病生存：P=0.007）最显著相关。在队列 2 中，高 K19 mRNA 水平的 HCC 表现出更高的 Snail、uPAR 和 MMP2 的 mRNA 水平（P<0.05）。与 K19 阴性 HCC 相比，K19 阳性 HCC 更常发生微血管侵犯、纤维性基质和更少的肿瘤包膜形成（P<0.05）。K19 表达是无病生存不良的显著独立预测因子（P=0.032）。
与其他干性相关蛋白相比，K19 与肿瘤侵袭性的临床病理特征密切相关。与 K19 阴性 HCC 相比，K19 阳性 HCC 表现出明显增加的 EMT 相关蛋白和 mRNA 表达，提示它们可能通过 EMT 相关基因的上调获得更具侵袭性的特征。
