Involvement of deterioration in S100C/A11-mediated pathway in resistance of human squamous cancer cell lines to TGFβ-induced growth suppression
Involvement of deterioration in S100C/A11-mediated pathway in resistance of human squamous cancer cell lines to TGFβ-induced growth suppression
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DOI：
10.1007/s00109-007-0180-7
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发表时间：
2007-05
期刊：
影响因子：
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通讯作者：
Hiroyuki Sonegawa;T. Nukui;Dai Li;M. Takaishi;M. Sakaguchi;N. Huh
中科院分区：
文献类型：
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作者：
Hiroyuki Sonegawa;T. Nukui;Dai Li;M. Takaishi;M. Sakaguchi;N. Huh
最近，我们证实S100C/A11是转化生长因子β抑制正常人角质形成细胞生长的重要途径。S100C/A11的核移植是该进程激活的标志。在本研究中，我们研究了S100C/A11及其功能伙伴Smad3和Smad4在细胞内的定位，探讨了该途径在人类鳞癌细胞系中的可能恶化。所有四种人鳞癌细胞系(A431、BSCC-93、DJM-1和HSC-5)都对转化生长因子β的生长抑制有抵抗力。在转化生长因子β作用的BSCC93、DJM1和HSC5细胞中，S100C/A11不能转移到细胞核，也不能诱导p21(WAF1)。核靶向S100C/A11的过表达可部分恢复转化生长因子β1对p21(WAF1)和p15(INK4B)的诱导和生长抑制。这些结果表明，S100C/A11途径的恶化导致癌细胞对转化生长因子β产生耐药。在A431细胞中，S100C/A11、Smad3和Smad4同时转移到细胞核，并在转化生长因子β作用下诱导p21(WAF1)。我们提供的证据表明，A431细胞对转化生长因子β的不耐药可能是因为转化生长因子β诱导的p21(WAF1)量不足以对抗在A431细胞中高表达的细胞周期蛋白A。因此，新发现的S100C/A11途径至少部分参与了诱导人鳞状细胞癌耐受转化生长因子β诱导的生长抑制，这被认为在许多人类癌症的发生和发展中发挥了关键作用。
Recently, we demonstrated that S100C/A11 comprises an essential pathway for growth suppression by TGFβ in normal human keratinocytes. Nuclear transfer of S100C/A11 was a hallmark of the activation of the process. In the present study, we examined the possible deterioration in the pathway in human squamous cancer cell lines, focusing on intracellular localization of S100C/A11 and its functional partners Smad3 and Smad4. All four human squamous cancer cell lines examined (A431, BSCC-93, DJM-1, and HSC-5) were resistant to growth suppression by TGFβ. In BSCC-93, DJM-1, and HSC-5 cells exposed to TGFβ, S100C/A11 was not transferred to the nuclei, and p21(WAF1) was not induced. Overexpression of nucleus-targeted S100C/A11 partially recovered induction of p21(WAF1) and p15(INK4B) and growth suppression by TGFβ1 in these cells. These results indicate that the deterioration in the S100C/A11-mediated pathway conferred upon the cancer cell lines resistance to TGFβ. In A431 cells, S100C/A11, Smad3, and Smad4 were simultaneously transferred to the nuclei, and p21(WAF1) was induced upon exposure to TGFβ. We provide evidence to indicate that refractoriness of A431 cells to TGFβ was probably because the amount of p21(WAF1) induced by TGFβ was insufficient to counteract cyclin A, which is highly overexpressed in A431 cells. Thus, the newly found S100C/A11-mediated pathway is at least partly involved in conferring upon human squamous cell cancers resistant to TGFβ-induced growth suppression, which is considered to play a critical role for the initiation and progression of many human cancers.