Heat shock factor 1 inhibits the mitochondrial apoptosis pathway by regulating second mitochondria-derived activator of caspase to promote pancreatic tumorigenesis.
Heat shock factor 1 inhibits the mitochondrial apoptosis pathway by regulating second mitochondria-derived activator of caspase to promote pancreatic tumorigenesis.
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热休克因子1通过调节第二种线粒体衍生的caspase激活剂抑制线粒体凋亡途径促进胰腺肿瘤发生
DOI：
10.1186/s13046-017-0537-x
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发表时间：
2017-05-08
期刊：
影响因子：
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通讯作者：
Yang J
中科院分区：
文献类型：
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作者：
Liang W;Liao Y;Zhang J;Huang Q;Luo W;Yu J;Gong J;Zhou Y;Li X;Tang B;He S;Yang J
热休克因子1（heat shock factor 1，HSF 1）是生物进化中相对保守的转录调控因子，在多种逆境胁迫条件下，热休克蛋白（heat shock proteins，HSPs）被激活并调控其表达。HSF 1在调节各种肿瘤的发展中也起着关键作用，但其在胰腺癌中的作用和具体的潜在机制尚不清楚。MethodsWe首先通过免疫组化检测HSF 1在胰腺癌组织中的表达，然后研究其临床意义。我们构建了HSF 1-siRNA，在体内外研究了HSF 1对胰腺癌细胞凋亡、增殖和细胞周期的调控作用及其机制。随后利用蛋白质芯片分析技术探讨了其分子调控途径。结果HSF 1在胰腺癌组织中高表达，其表达水平与胰腺癌的分化程度和预后密切相关。HSF 1基因沉默后，胰腺癌细胞增殖能力下降，凋亡细胞比例增加，线粒体膜电位下降，细胞阻滞于G 0/G1期。在分子机制方面，证实了HSF 1通过调控SMAC抑制胰腺癌细胞线粒体凋亡，促进胰腺肿瘤的发生。SMAC沉默逆转的影响HSF 1 silencing.ConclusionOur研究提供的证据表明，HSF 1作为一种新的癌基因在胰腺肿瘤的功能，并牵连作为胰腺癌的诊断和治疗的目标。
BackgroundAs a relatively conservative transcriptional regulator in biological evolution, heat shock factor 1 (HSF1) is activated by, and regulates the expression of heat shock proteins (HSPs) in response to a variety of stress conditions. HSF1 also plays a key role in regulating the development of various tumors; however, its role in pancreatic cancer and the specific underlying mechanism are not clear.MethodsWe first examined HSF1 expression in pancreatic cancer tissues by immunohistochemistry, and then studied its clinical significance. We then constructed HSF1-siRNA to investigate the potential of HSF1 to regulate apoptosis, proliferation and the cell cycle of pancreatic cancer cells and the underlying mechanism both in vitro and in vivo. Protein chip analysis was used subsequently to explore the molecular regulation pathway. Finally, second mitochondria-derived activator of caspase (SMAC)-siRNA was used to validate the signaling pathway.ResultsHSF1 was highly expressed in pancreatic cancer tissues and the level of upregulation was found to be closely related to the degree of pancreatic cancer differentiation and poor prognosis. After HSF1-silencing, we found that pancreatic cancer cell proliferation decreased both in vitro and in vivo and the apoptotic cell ratio increased, while the mitochondrial membrane potential decreased, and the cells were arrested at the G0/G1 phase. In terms of the molecular mechanism, we confirmed that HSF1 regulated SMAC to inhibit mitochondrial apoptosis in pancreatic cancer cells, and to promote the occurrence of pancreatic tumors. SMAC silencing reversed the effects of HSF1 silencing.ConclusionOur study provides evidence that HSF1 functions as a novel oncogene in pancreatic tumors and is implicated as a target for the diagnosis and treatment of pancreatic cancer.