Department of Pathology, Center for Chronic Metabolic Disease, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemoon-gu, Seoul 120-752, Republic of Korea.
Exp Mol Pathol. 2011 Feb;90(1):66-73. doi: 10.1016/j.yexmp.2010.10.003. Epub 2010 Oct 20.
Hepatocellular carcinomas (HCCs) with expression of stem/progenitor cell markers including CD133 have been reported to have more aggressive biological behavior, and epithelial-mesenchymal transition (EMT), closely related invasion, has been suggested to generate cancer stem cells. To elucidate biological characteristics of HCCs expressing CD133, we evaluated migration assay and the mRNA expression levels of CD133, invasion-associated genes [urokinase plasminogen activator receptor (uPAR), villin 2 (VIL2), and MMP1 and MMP2], and EMT regulators (Snail, Slug, Twist, E-cadherin, and N-cadherin) by real-time PCR in HCC cell lines including HepG2, Hep3B, Huh7, PLC/RFP/6, SNU423, SNU449, and SNU475. Same genes and pathological features were also investigated in 49 samples of hepatitis B virus-related human HCCs. In all HCC cell lines studied, CD133-positive cells showed higher cell migration activity and up-regulated invasion- and EMT-associated genes with increased N-cadherin and decreased E-cadherin expressions compared to CD133-negative cells. The human HCCs were divided into the CD133-high group (top 40%) and the CD133-low group (bottom 40%) according to the level of CD133 mRNA. The CD133-high group showed relatively frequent vascular invasion and significantly higher expression of invasion-associated genes [uPAR (p=0.002), MMP1 (p=0.01), and MMP2 (p=0.003)] and EMT regulators [Snail (p=0.002) and Twist (p=0.0003)] compared to the CD133-low group. In conclusion, our results suggest that there is a subtype of HCC with high expression of CD133, which might have more invasive characteristics by up-regulation of invasion-associated genes and EMT-associated genes.
肝细胞癌 (HCCs) 表达干细胞/祖细胞标志物，包括 CD133，已被报道具有更具侵袭性的生物学行为，上皮-间充质转化 (EMT) 与侵袭密切相关，被认为产生癌症干细胞。为了阐明表达 CD133 的 HCC 的生物学特性，我们通过实时 PCR 评估了迁移试验以及 HCC 细胞系 [尿激酶纤溶酶原激活物受体 (uPAR)、villin 2 (VIL2)、MMP1 和 MMP2] 和 EMT 调节剂 (Snail、Slug、Twist、E-钙粘蛋白和 N-钙粘蛋白) 的 CD133 表达水平，包括 HepG2、Hep3B、Huh7、PLC/RFP/6、SNU423、SNU449 和 SNU475。在 49 例乙型肝炎病毒相关人类 HCC 样本中也研究了相同的基因和病理特征。在所有研究的 HCC 细胞系中，与 CD133-阴性细胞相比，CD133 阳性细胞表现出更高的细胞迁移活性，并上调了侵袭和 EMT 相关基因，同时表达了更多的 N-钙粘蛋白和更少的 E-钙粘蛋白。根据 CD133 mRNA 水平，将人 HCC 分为 CD133-高组 (前 40%) 和 CD133-低组 (后 40%)。与 CD133-低组相比，CD133-高组表现出相对频繁的血管侵犯，侵袭相关基因 [uPAR(p=0.002)、MMP1(p=0.01) 和 MMP2(p=0.003)] 和 EMT 调节剂 [Snail(p=0.002) 和 Twist(p=0.0003)] 的表达显著更高。总之，我们的结果表明，存在一种 CD133 高表达的 HCC 亚型，通过上调侵袭相关基因和 EMT 相关基因，可能具有更具侵袭性的特征。
