SKI and MEL1 Cooperate to Inhibit Transforming Growth Factor-β Signal in Gastric Cancer Cells*
SKI and MEL1 Cooperate to Inhibit Transforming Growth Factor-β Signal in Gastric Cancer Cells*
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DOI：
10.1074/jbc.m808989200
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发表时间：
2009-01
影响因子：
4.8
通讯作者：
Mami Takahata;Yasumichi Inoue;H. Tsuda;I. Imoto;D. Koinuma;M. Hayashi;T. Ichikura;T. Yamori;K. Nagasaki;Mika Yoshida;M. Matsuoka;K. Morishita;K. Yuki;A. Hanyu;K. Miyazawa;J. Inazawa;K. Miyazono;T. Imamura
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文献类型：
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作者：
Mami Takahata;Yasumichi Inoue;H. Tsuda;I. Imoto;D. Koinuma;M. Hayashi;T. Ichikura;T. Yamori;K. Nagasaki;Mika Yoshida;M. Matsuoka;K. Morishita;K. Yuki;A. Hanyu;K. Miyazawa;J. Inazawa;K. Miyazono;T. Imamura
染色体扩增常发生在实体瘤中，并与不良预后相关。一些报告证明了在癌症发展过程中同一扩增子中致癌因子的协同作用。然而，这些因素之间的功能相关性仍不清楚。转化生长因子（Transforming growth factor，TGF）-β信号在细胞停滞和正常上皮分化中起重要作用，在许多恶性肿瘤中发现了TGF-β信号的改变。在这里，我们证明了TGF-β信号传导的转录辅抑制因子SKI和MDS 1/EVI 1样基因1（MEL 1）通过1p36.32的染色体共扩增在MKN 28胃癌细胞中异常表达。SKI和MEL 1敲低协同恢复了MKN 28细胞中的TGF-β反应性，并减少了体内肿瘤生长。MEL 1与SKI相互作用，通过稳定TGF-β靶基因启动子上的失活Smad 3-SKI复合物来抑制TGF-β信号转导。这些发现揭示了一种新的机制，其中不同的转录辅阻遏物被共扩增并在功能上相互作用，并为胃癌治疗提供了分子靶点。
Chromosomal amplification occurs frequently in solid tumors and is associated with poor prognosis. Several reports demonstrated the cooperative effects of oncogenic factors in the same amplicon during cancer development. However, the functional correlation between the factors remains unclear. Transforming growth factor (TGF)-β signaling plays important roles in cytostasis and normal epithelium differentiation, and alterations in TGF-β signaling have been identified in many malignancies. Here, we demonstrated that transcriptional co-repressors of TGF-β signaling, SKI and MDS1/EVI1-like gene 1 (MEL1), were aberrantly expressed in MKN28 gastric cancer cells by chromosomal co-amplification of 1p36.32. SKI and MEL1 knockdown synergistically restored TGF-β responsiveness in MKN28 cells and reduced tumor growth in vivo. MEL1 interacted with SKI and inhibited TGF-β signaling by stabilizing the inactive Smad3-SKI complex on the promoter of TGF-β target genes. These findings reveal a novel mechanism where distinct transcriptional co-repressors are co-amplified and functionally interact, and provide molecular targets for gastric cancer treatment.