Expression and role of Bcl-xL in human hepatocellular carcinomas
Expression and role of Bcl-xL in human hepatocellular carcinomas
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DOI：
10.1053/jhep.2001.25387
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发表时间：
2001-07-01
期刊：
影响因子：
13.5
通讯作者：
Takahashi, H
中科院分区：
文献类型：
--
作者：
Takehara, T;Liu, XL;Takahashi, H
转化的肝细胞在体内生长过程中经受住了各种凋亡的伤害。然而，抑制细胞凋亡和支持细胞存活的分子机制还不是很清楚。在本研究中，我们研究了抗细胞凋亡基因Bcl2家族成员Bclxl在人肝细胞癌中的表达及其作用。人肝癌细胞株HepG2、Hep3B和HuH7均高水平表达BclxL蛋白，但这些细胞均不表达Bcl2。反义寡核苷酸下调bc l-xl激活细胞凋亡，以应对星状孢子素治疗或血清饥饿诱导的细胞应激。单独异位表达转录活性P53不足以激活P53缺失的Hep3B细胞的凋亡，但当内源性的Bclxl同时被反义寡核苷酸抑制时，可诱导这些细胞的凋亡。免疫组织化学和Western印迹分析结果显示，bclxl在20例手术切除的人肝细胞癌组织中均有表达，且部分肝细胞癌组织中bclxl的表达水平高于癌旁肝组织和正常肝组织。我们认为，在人肝癌细胞中表达的Bclxl可抑制星形孢子素治疗、血清饥饿和P53激活等多种细胞应激引起的细胞凋亡，并可能在肝癌细胞的存活中发挥重要作用。
Transformed hepatocytes survive various apoptotic insults during their growth in vivo. However, molecular mechanisms that inhibit apoptosis and support their survival are not well understood. In this study, we investigated the expression and role of Bcl-xL, an antiapoptotic member of the Bcl-2 family, in human hepatocellular carcinoma (HCC). The Bcl-xL protein was expressed in HepG2, Hep3B, and Huh7 human hepatoma cell lines at high levels, but none of these cells expressed Bcl-2. Down-modulation of Bcl-xL by antisense oligonucleotide activated apoptosis in HepG2 cells in response to cellular stresses induced by staurosporine treatment or by serum starvation. Ectopic expression of transcriptionally active p53 alone was not sufficient for the activation of apoptosis in p53-null Hep3B cells, but apoptosis was induced when endogenous Bcl-xL was simultaneously inhibited by antisense oligonucleotide in these cells. Bcl-xL was expressed in all 20 surgically resected human HCC tissues when examined by Western blot analysis and immunohistochemistry, and levels of its expression were higher in a subset of HCC tissues than those of adjacent nontumor liver tissues or normal livers. We conclude that Bcl-xL expressed in human HCC cells inhibits apoptosis produced by various cellular stresses, such as staurosporine treatment, serum starvation, and p53 activation, and may play an important role in their survival.