p63α protein up-regulates heat shock protein 70 expression via E2F1 transcription factor 1, promoting Wasf3/Wave3/MMP9 signaling and bladder cancer invasion
p63α protein up-regulates heat shock protein 70 expression via E2F1 transcription factor 1, promoting Wasf3/Wave3/MMP9 signaling and bladder cancer invasion
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刺猬活动水平融合抑制的抑制剂对于颅骨发育过程中的成骨增殖和分化至关重要
DOI：
10.1074/jbc.m117.792010
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发表时间：
2017-09-22
影响因子：
4.8
通讯作者：
Huang, Chuanshu
中科院分区：
文献类型：
--
作者：
Jin, Honglei;Xie, Qipeng;Huang, Chuanshu
膀胱癌(BC)是美国第六大常见癌症，也是泌尿系统恶性肿瘤患者的头号死因。这使得确定侵袭性调节因子(S)/效应因子(S)作为治疗BC的潜在治疗靶点成为当务之急。P63是抑癌基因/蛋白P53家族中的一员，在上皮组织分化中起作用，被认为具有肿瘤抑制作用。然而，目前还不清楚p63是否以及如何在BC细胞肿瘤发生后的侵袭中发挥作用。在这里，我们发现p63α蛋白水平在小鼠高侵袭性BC组织中比在正常组织中高得多。我们的结果还表明，p63α对热休克蛋白70(Hsp70)的表达至关重要，并随后增加了BC的侵袭能力。机制实验表明，p63α可以转录上调Hsp70的表达，从而通过Hsp70/Wasf3/Wave3/MMP9轴促进BC细胞的侵袭。进一步的研究表明，E2F转录因子1(E2F1)介导了p63α过表达诱导的Hsp70转录。我们还发现，p63α的过表达激活了E2F1的转录，这似乎是由p63α和E2F1共同刺激的。总之，我们的结果表明，p63α是BC细胞在肿瘤发生后侵袭的积极调节因子，为深入了解p63α在BC中的生物学功能提供了重要的见解，并支持P63α可能是侵袭性BC治疗的潜在靶点的观点。
Bladder cancer (BC) is the sixth most common cancer in the United States and is the number one cause of death among patients with urinary system malignancies. This makes the identification of invasive regulator(s)/effector(s) as the potential therapeutic targets for managing BC a high priority. p63 is a member of the p53 family of tumor suppressor genes/proteins, plays a role in the differentiation of epithelial tissues, and is believed to function as a tumor suppressor. However, it remains unclear whether and how p63 functions in BC cell invasion after tumorigenesis. Here, we show that p63 alpha protein levels were much higher in mouse high-invasive BC tissues than in normal tissues. Our results also revealed that p63 alpha is crucial for heat shock protein 70 (Hsp70) expression and subsequently increases the ability of BC invasion. Mechanistic experiments demonstrated that p63 alpha can transcriptionally up-regulate Hsp70 expression, thereby promoting BC cell invasion via the Hsp70/Wasf3/Wave3/MMP-9 axis. Wefurther show that E2F transcription factor 1 (E2F1) mediates p63 alpha overexpressioninduced Hsp70 transcription. We also found that p63 alpha overexpression activates E2F1 transcription, which appears to be stimulated by p63 alpha together with E2F1. Collectively, our results demonstrate that p63 alpha is a positive regulator of BC cell invasion after tumorigenesis, providing significant insights into the biological function of p63 alpha in BC and supporting the notion that p63 alpha might be a potential target for invasive BC therapy.