Hepatitis C Virus-Induced Cancer Stem Cell-Like Signatures in Cell Culture and Murine Tumor Xenografts
Hepatitis C Virus-Induced Cancer Stem Cell-Like Signatures in Cell Culture and Murine Tumor Xenografts
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DOI：
10.1128/jvi.05920-11
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发表时间：
2011-12-01
影响因子：
5.4
通讯作者：
Houchen, Courtney W.
中科院分区：
文献类型：
--
作者：
Ali, Naushad;Allam, Heba;Houchen, Courtney W.
丙型肝炎病毒（HCV）感染是肝细胞癌（HCC）发生的重要危险因素。与大多数实体瘤相似，HCC被认为含有低分化的癌症干细胞样细胞（CSC），其启动肿瘤发生并赋予对化疗的抗性。在这些研究中，我们证明了HCV亚基因组复制子在培养细胞中的表达导致CSC性状的获得。这些特征包括双皮质素和CaM激酶样-1（DCAMKL-1）、Lgr 5、CD 133、甲胎蛋白、细胞角蛋白-19（CK 19）、Lin 28和c-Myc的表达增强。相反，来自这些细胞的复制子的治愈会导致这些因子的表达减少。假定的干细胞标志物DCAMKL-1也响应于多能性因子盒的过表达而升高。通过荧光激活细胞分选（FACS）从肝癌细胞系分离的DCAMKL-1阳性细胞在基质胶中形成球状体。HCV RNA丰度和NS 5 B水平通过小干扰RNA（siRNA）-引导的DCAMKL-1消耗而显著降低。我们进一步证明，HCV复制子表达细胞启动不同的肿瘤表型相比，缺乏复制子的亲本细胞启动的肿瘤。这种HCV诱导的表型的特征在于DCAMKL-1、CK 19、甲胎蛋白和活性c-Src的高水平表达/共表达。通过对HCV阳性患者的肝组织和肝组织微阵列的分析获得的结果重申了这些观察结果。总之，慢性HCV感染似乎通过诱导DCAMKL-1和肝祖细胞和干细胞相关因子使细胞倾向于获得癌症干细胞样特征的途径。DCAMKL-1也代表了一种新的细胞靶点，用于对抗HCV诱导的肝癌发生。
Hepatitis C virus (HCV) infection is a prominent risk factor for the development of hepatocellular carcinoma (HCC). Similar to most solid tumors, HCCs are believed to contain poorly differentiated cancer stem cell-like cells (CSCs) that initiate tumorigenesis and confer resistance to chemotherapy. In these studies, we demonstrate that the expression of an HCV subgenomic replicon in cultured cells results in the acquisition of CSC traits. These traits include enhanced expression of doublecortin and CaM kinase-like-1 (DCAMKL-1), Lgr5, CD133, alpha-fetoprotein, cytokeratin-19 (CK19), Lin28, and c-Myc. Conversely, curing of the replicon from these cells results in diminished expression of these factors. The putative stem cell marker DCAMKL-1 is also elevated in response to the overexpression of a cassette of pluripotency factors. The DCAMKL-1-positive cells isolated from hepatoma cell lines by fluorescence-activated cell sorting (FACS) form spheroids in Matrigel. The HCV RNA abundance and NS5B levels are significantly reduced by the small interfering RNA (siRNA)-led depletion of DCAMKL-1. We further demonstrate that HCV replicon-expressing cells initiate distinct tumor phenotypes compared to the tumors initiated by parent cells lacking the replicon. This HCV-induced phenotype is characterized by high-level expression/ coexpression of DCAMKL-1, CK19, alpha-fetoprotein, and active c-Src. The results obtained by the analysis of liver tissues from HCV-positive patients and liver tissue microarrays reiterate these observations. In conclusion, chronic HCV infection appears to predispose cells toward the path of acquiring cancer stem cell-like traits by inducing DCAMKL-1 and hepatic progenitor and stem cell-related factors. DCAMKL-1 also represents a novel cellular target for combating HCV-induced hepatocarcinogenesis.