Resistance to TGF-β1 correlates with aberrant expression of TGF-β receptor II in human B-cell lymphoma cell lines
Resistance to TGF-β1 correlates with aberrant expression of TGF-β receptor II in human B-cell lymphoma cell lines
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DOI：
10.1182/blood-2006-06-032128
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发表时间：
2007-06-15
期刊：
影响因子：
20.3
通讯作者：
Longo, Dan L.
中科院分区：
文献类型：
--
作者：
Chen, Gang;Ghosh, Paritosh;Longo, Dan L.
对肿瘤细胞中转化生长因子（TGF）-β 1介导的生长抑制的抗性通常与TGF-β受体的功能丧失相关。在这里，我们描述了两个B细胞淋巴瘤细胞系（DB和RL），不同的敏感性TGF-β 1介导的生长抑制。TGF-β 1抗性细胞系DB与TGF-β应答细胞系RL相比缺乏功能性TGF-β受体II（T β RII），而两种细胞系具有相当水平的受体I（T β RI）。功能性T β RII的缺乏与TGF-β 1诱导的磷酸化Smad3和磷酸化Smad2核转位的缺乏、p21（Cip1/WAF1）核表达的缺乏以及DB细胞中c-Myc的下调相关。转染野生型，而不是C-末端截短的形式的T β RII，使DB细胞系对TGF-β 1介导的生长抑制有反应。DB细胞中T β RII基因的分析显示T β RII信息的缺失，这在5'-氮杂胞苷处理后被逆转，表明启动子甲基化可能是基因沉默的原因。启动子分析揭示了与基因沉默相关的-25和-140处的CpG甲基化。这些数据表明，启动子甲基化在T β RII基因沉默和随后某些B细胞淋巴瘤细胞产生TGF-β 1抗性表型中起重要作用。
Resistance to transforming growth factor (TGF)-beta 1-mediated growth suppression in tumor cells is often associated with the functional loss of TGF-beta receptors. Here we describe two B-cell lymphoma cell lines (DB and RL) that differ in their sensitivity to TGF-beta 1-mediated growth suppression. The TGF-beta 1-resistant cell line DB lacked functional TGF-beta receptor II (T beta RII) in contrast to the TGF-beta-responsive cell line RL, whereas both cell lines had comparable levels of receptor I (T beta RI). Lack of functional T beta RII was correlated with the lack of TGF-beta 1-induced nuclear translocation of phospho-Smad3 and phospho-Smad2, the lack of nuclear expression of p21(Cip1/WAF1), and the down-regulation of c-Myc in DB cells. Transfection of wild-type, but not a C-terminal-truncated, form of T beta RII rendered the DB cell line responsive to TGF-beta 1-mediated growth suppression. Analysis of the T beta RII gene in DB cells revealed the absence of T beta RII message, which was reversed upon 5'-azacytidine treatment, indicating that the promoter methylation might be the cause of gene silencing. Promoter analysis revealed CpG methylations at -25 and - 140 that correlated with the gene silencing. These data suggest that promoter methylation plays an important role in T beta RII gene silencing and subsequent development of a TGF-beta 1-resistant phenotype by some B-cell lymphoma cells.