JBC：前列腺癌转移的开关

　　

生物通报道：局限在前列腺中的前列腺癌威胁并不大，但当癌细胞扩散到骨骼、肺部、肝脏等区域后这种癌症就可能致命。此前有研究显示，E-钙粘素（E-Cadherin）缺失是前列腺癌转移的必要条件。科罗拉多大学癌症中心的一项新研究，首次揭示了调控E-Cadherin合成的开关——转录因子SPDEF，这一开关能够在前列腺癌模型中促使或阻止癌转移。文章发表在Journal of Biological Chemistry杂志上。

“在缺乏E-Cadherin时，肿瘤细胞能够离开周围组织，轻易进入循环系统，并转移到新位点继续生长。我们在缺乏E-Cadherin的前列腺肿瘤中增加SPDEF，发现这种转录因子可以使肿瘤重新表达E-Cadherin。此时，肿瘤细胞再次锚定下来，丧失了转移能力，”文章的资深作者，科罗拉多大学医学院的Hari Koul教授说。

近来越来越多的证据表明，在许多癌症中E-Cadherin缺乏都是癌症转移的前兆，因此这一发现不仅有助于治疗前列腺癌，也对其他疾病有着深远影响。研究人员此前曾发现，SPDEF能够在体外和体内抑制癌转移。为了更好的了解SPDEF在前列腺癌转移中的作用机制，他们在这项新研究中解析了SPDEF和E-Cadherin表达的关系。

研究显示，调节E-Cadherin和SPDEF对癌细胞的侵袭能力有着相似的影响。Koul及其同事首次向人们展示，增减SPDEF直接影响了E-Cadherin的水平，增强SPDEF的表达能够提高E-Cadherin表达，而下调SPDEF会减少E-Cadherin的表达。此外，研究人员发现SPDEF会与E-Cadherin的启动子区域结合，在前列腺癌细胞中直接诱导E-Cadherin的转录。

研究人员在SPDEF存在的情况下，人为降低了E-Cadherin的水平，发现癌细胞依然能够转移并侵袭新的组织。这说明SPDEF本身并不影响癌转移，这种转录引子只能通过调控E-Cadherin起作用。研究人员指出，这是一个单项开关，SPDEF调控着E-Cadherin的表达，但E-Cadherin的表达水平并不会影响SPDEF。

“总的来说，我们发现SPDEF可以通过调控E-Cadherin来抑制前列腺癌的转移，”Koul说。“这项研究首次证明E-Cadherin的表达需要SPDEF。”

研究人员认为，可以通过在癌细胞中增加SPDEF的水平，来弥补癌细胞中的E-Cadherin缺失。“这是一项标志性的研究，”Koul说。“人们发现了癌转移的前提，而现在我们又掌握新的知识，可以去除这一必要条件，进而阻断前列腺癌的转移。”

 

（生物通编辑：叶予）

生物通推荐原文摘要：

The transcription factor SPDEF is required for E-Cadherin expression in prostate cancer cells

Loss of E-Cadherin is one of the key steps in tumor progression. Our previous studies demonstrate that SAM Pointed Domain ETS transcription Factor (SPDEF) inhibited prostate cancer metastasis in vitro and in vivo. In the present study, we evaluated the relationship between SPDEF and E-Cadherin expression in an effort to better understand the mechanism of action of SPDEF in prostate tumor-cell invasion and metastasis. Results presented here in demonstrate a direct correlation between expression of E-Cadherin and SPDEF in prostate cancer cells. Additional data demonstrate that modulation of E-Cadherin and SPDEF had similar effects of cell migration/invasion. In addition, siRNA mediated knock down of E-Cadherin was sufficient to block the effects of SPDEF on cell migration and invasion. We also show that stable forced expression of SPDEF results in increased expression of E-Cadherin, while as, down-regulation of SPDEF decreased E-Cadherin expression. In addition, we demonstrate that SPDEF expression is not regulated by E-Cadherin. Moreover, our chromatin immuno-precipitation and luciferase reporter assay revealed that SPDEF occupies E-Cadherin promoter site and acts a direct transcriptional inducer of E-Cadherin in prostate cancer cells. Taken together, to the best of our knowledge these are the first studies demonstrating requirement of SPDEF for expression of E-cadherin, an essential epithelial cell junction protein. Given that loss of E-Cadherin is a central tenant in tumor metastasis, results of our studies, by providing a new mechanism for regulation of E-cadherin expression, could have far-reaching impact.