Heat-shock factor 2 is a suppressor of prostate cancer invasion.
Heat-shock factor 2 is a suppressor of prostate cancer invasion.
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DOI：
10.1038/onc.2015.241
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发表时间：
2016-04-07
期刊：
影响因子：
8
通讯作者：
Nees M
中科院分区：
文献类型：
--
作者：
Björk JK;Åkerfelt M;Joutsen J;Puustinen MC;Cheng F;Sistonen L;Nees M
热休克因子（HSFs）是细胞存活的关键转录调节因子。虽然HSF1已被确定为致癌的驱动因素，但HSF2尚未在恶性肿瘤中进行探索。在这里，我们报告说，HSF2抑制前列腺癌（PrCa）的肿瘤侵袭。在三维器官型培养和体内异种移植绒毛尿囊膜模型中，HSF2敲低干扰类器官分化并促进侵袭性。基因表达谱和功能研究表明，对肿瘤进展的影响的分子机制源于HSF2引导腺泡形态发生和侵袭之间的转换。这是通过调节与例如GT3活性、细胞粘附、细胞外基质和肌动蛋白细胞骨架动力学相关的基因来实现的。重要的是，低HSF2表达与PrCa患者的高Gleason评分、转移和低生存率相关，突出了我们研究结果的临床意义。最后，该研究扩展到PrCa之外，揭示了HSF2的表达在广泛的癌症类型中降低。这项研究提供了第一个证据表明HSF2作为一个抑制剂的侵袭在人类恶性肿瘤。
Heat-shock factors (HSFs) are key transcriptional regulators in cell survival. Although HSF1 has been identified as a driver of carcinogenesis, HSF2 has not been explored in malignancies. Here, we report that HSF2 suppresses tumor invasion of prostate cancer (PrCa). In three-dimensional organotypic cultures and the in vivo xenograft chorioallantoic membrane model HSF2 knockdown perturbs organoid differentiation and promotes invasiveness. Gene expression profiling together with functional studies demonstrated that the molecular mechanism underlying the effect on tumor progression originates from HSF2 steering the switch between acinar morphogenesis and invasion. This is achieved by the regulation of genes connected to, for example, GTPase activity, cell adhesion, extracellular matrix and actin cytoskeleton dynamics. Importantly, low HSF2 expression correlates with high Gleason score, metastasis and poor survival of PrCa patients, highlighting the clinical relevance of our findings. Finally, the study was expanded beyond PrCa, revealing that the expression of HSF2 is decreased in a wide range of cancer types. This study provides the first evidence for HSF2 acting as a suppressor of invasion in human malignancies.