Aberrant expression of serine/threonine kinase Pim-3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines
Aberrant expression of serine/threonine kinase Pim-3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines
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DOI：
10.1002/ijc.20719
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发表时间：
2005-03-20
影响因子：
6.4
通讯作者：
Mukaida, N
中科院分区：
文献类型：
--
作者：
Fujii, C;Nakamoto, Y;Mukaida, N
大多数人肝细胞癌病例在持续慢性感染人B型肝炎病毒或丙型肝炎病毒后发生，推测宿主反应在此过程中起主要作用。为了概括这一过程，我们利用B病毒表面抗原转基因小鼠建立了肝细胞癌小鼠模型。为了确定在这个模型中与肝癌发生相关的基因，我们比较了癌前病变周围的肝细胞癌组织和对照肝组织之间的基因表达模式，通过使用荧光差异显示分析。在癌前病变中差异表达的基因中，我们专注于原癌基因Pim家族的成员Pim-3，因为其对肝癌发生的贡献仍然未知。此外，全长人Pim-3 cDNA的核苷酸序列的不可用性促使我们从人肝癌细胞系HepG 2构建的cDNA文库中克隆它。所获得的2，392 bp的人Pim-3 cDNA编码由326个氨基酸组成的预测开放阅读框架。Pim-3 mRNA在人肝癌细胞系中选择性表达，而在正常肝组织中不表达。此外，Pim-3蛋白在人肝癌组织和细胞系中检测到，而在正常肝细胞中未检测到。RNA干扰技术阻断Pim-3基因可抑制人肝癌细胞增殖，促进细胞凋亡。这些观察结果表明，异常表达的Pim-3可以引起自主细胞增殖或阻止肝癌细胞系的凋亡。(C)2004年威利-利斯。Inc.
Most cases of human hepatocellular carcinoma develop after persistent chronic infection with human hepatitis B virus or hepatitis C virus, and host responses are presumed to have major roles in this process. To recapitulate this process, we have developed the mouse model of hepatocellular carcinoma using hepatitis B virus surface antigen transgenic mice. To identify the genes associated with hepatocarcinogenesis in this model, we compared the gene expression patterns between pre-malignant lesions surrounded by hepatocellular carcinoma tissues and control liver tissues by using a fluorescent differential display analysis. Among the genes that were expressed differentially in the pre-malignant lesions, we focused on Pim-3, a member of a proto-oncogene Pim family, because its contribution to hepatocarcinogenesis remains unknown. Moreover, the unavailability of the nucleotide sequence of full-length human Pim-3 cDNA prompted us to clone it from the cDNA library constructed from a human hepatoma cell line, HepG2. The obtained 2,392 bp human Pim-3 cDNA encodes a predicted open reading frame consisting of 326 amino acids. Pim-3 mRNA was selectively expressed in human hepatoma cell lines, but not in normal liver tissues. Moreover, Pim-3 protein was detected in human hepatocellular carcinoma tissues and cell lines but not in normal hepatocytes. Furthermore, cell proliferation was attenuated and apoptosis was enhanced in human hepatoma cell lines by the ablation of Pim-3 gene with RNA interference. These observations suggest that aberrantly expressed Pim-3 can cause autonomous cell proliferation or prevent apoptosis in hepatoma cell lines. (C) 2004 Wiley-Liss. Inc.