Heat-shock transcription factor HSF1 has a critical role in human epidermal growth factor receptor-2-induced cellular transformation and tumorigenesis.
Heat-shock transcription factor HSF1 has a critical role in human epidermal growth factor receptor-2-induced cellular transformation and tumorigenesis.
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热休克转录因子 HSF1 在人表皮生长因子受体 2 诱导的细胞转化和肿瘤发生中发挥关键作用。
DOI：
10.1038/onc.2010.277
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发表时间：
2010-09-16
期刊：
影响因子：
8
通讯作者：
Sherman, M. Y.
中科院分区：
文献类型：
--
作者：
Meng, L.;Gabai, V. L.;Sherman, M. Y.
最近证明热休克转录因子 HSF1 在与 Ras 激活或 p53 失活相关的肿瘤发展中发挥关键作用。在这里，我们表明HSF1是由负责侵袭性乳腺肿瘤的HER2癌基因诱导的细胞转化和肿瘤发生所必需的。 HER2表达后，未转化的人乳腺上皮细胞MCF-10A发生肿瘤转化，在培养物中形成病灶，并在裸鼠异种移植物中形成肿瘤。然而，敲低 HSF1 的 MCF-10A 细胞中 HER2 的表达不会导致异种移植物中病灶形成或肿瘤生长。 HSF1 下调的抗肿瘤作用与 HER2 诱导的 CDK 抑制剂 p21 的积累和有丝分裂调节剂生存素的减少有关，从而导致生长抑制和细胞衰老。事实上，p21 敲除或生存素过度表达都减轻了 HSF1 敲除的这些影响。某些人类 HER2 阳性乳腺癌细胞系的增殖也需要 HSF1，因为它的敲低会导致 p21 上调和/或生存素下降，从而导致生长停滞。使用小分子量热休克反应抑制剂 NZ28 观察到类似的效果。 HSF1 敲低对 HER2 表达细胞生长停滞和衰老的影响与 Hsp72 和 Hsp27 的下调有关。因此，HSF1 对于 HER2 表达细胞的增殖至关重要，很可能是因为它维持 HSP 的水平，而 HSP 反过来又控制衰老 p21 和生存素的调节因子。
The heat shock transcription factor HSF1 was recently demonstrated to play a key role in the development of tumors associated with activation of Ras or inactivation of p53. Here we show that HSF1 is required for cell transformation and tumorigenesis induced by HER2 oncogene responsible for aggressive breast tumors. Upon expression of HER2, untransformed human mammary epithelial cells MCF-10A underwent neoplastic transformation, formed foci in culture and tumors in nude mouse xenografts. However, expression of HER2 in MCF-10A cells with knockdown of HSF1 did not cause either foci formation or tumor growth in xenografts. The anti-tumorigenic effect of downregulation of HSF1 was associated with HER2-induced accumulation of the CDK inhibitor p21 and decrease of the mitotic regulator survivin, which resulted in growth inhibition and cell senescence. In fact, either knockout of p21 or overexpression of survivin alleviated these effects of HSF1 knockdown. Proliferation of certain human HER2-postitive breast cancer lines also requires HSF1, since its knockdown led to upregulation of p21 and/or drop of survivin, precipitating growth arrest. Similar effects were observed with a small molecular weight inhibitor of the heat shock response NZ28. Effects of HSF1 knockdown on growth arrest and senescence of HER2-expressing cells were associated with downregulation of Hsp72 and Hsp27. Therefore, HSF1 is critical for proliferation of HER2-expressing cells, most likely since it maintains levels of HSPs, which in turn control regulators of senescence p21 and survivin.
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影响因子：
44.1
作者：
Cai, L;Zhu, D
通讯作者：
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64.5
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作者：
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