Human RecQL4 helicase plays critical roles in prostate carcinogenesis.
Human RecQL4 helicase plays critical roles in prostate carcinogenesis.
复制标题
DOI：
10.1158/0008-5472.can-10-1743
复制
发表时间：
2010-11-15
期刊：
影响因子：
11.2
通讯作者：
Balajee AS
中科院分区：
文献类型：
--
作者：
Su Y;Meador JA;Calaf GM;Proietti De-Santis L;Zhao Y;Bohr VA;Balajee AS
前列腺癌是西方国家男性癌症相关死亡的第二大原因。在这里，我们报告说，人类RecQL 4解旋酶，这是牵连在一个子集的癌症倾向的Rothmund-Thomson综合征的发病机制，是高度升高的转移性前列腺癌细胞系。在人前列腺肿瘤组织中也检测到RecQL 4表达增加，作为肿瘤等级的函数，在转移性肿瘤样品中具有最高表达水平，表明RecQL 4可能是晚期前列腺癌的潜在预后因素。通过siRNA和shRNA载体对RecQL 4的瞬时和稳定抑制显著降低了转移性前列腺癌细胞的生长和存活，表明RecQL 4是前列腺癌细胞的促存活因子。RecQL 4抑制导致聚（ADP）核糖聚合物（PAR）合成增加，并且RecQL 4抑制的前列腺癌细胞以PARP-1依赖性方式经历广泛的凋亡性死亡。最值得注意的是，转移性前列腺癌细胞中的RecQL 4敲低显著降低了它们的体外细胞侵袭性和体内致瘤性，表明RecQL 4对于前列腺癌促进是必需的。Rb和E2 F1蛋白与RecQL 4启动子的直接相互作用的观察表明Rb-E2 F1途径可能调节RecQL 4表达。总的来说，我们的研究表明RecQL 4是前列腺癌发生的重要因素。
Prostate cancer is the second leading cause of cancer associated deaths among men in the western countries. Here, we report that human RecQL4 helicase, which is implicated in the pathogenesis of a subset of cancer prone Rothmund-Thomson syndrome, is highly elevated in metastatic prostate cancer cell lines. Increased RecQL4 expression was also detected in human prostate tumor tissues as a function of tumor grade with the highest expression level in metastatic tumor samples suggesting that RecQL4 may be a potential prognostic factor for advanced stage of prostate cancer. Transient and stable suppression of RecQL4 by siRNA and shRNA vectors drastically reduced the growth and survival of metastatic prostate cancer cells indicating that RecQL4 is a pro-survival factor for prostate cancer cells. RecQL4 suppression led to increased poly (ADP) ribose polymer (PAR) synthesis and RecQL4 suppressed prostate cancer cells underwent an extensive apoptotic death in a PARP-1 dependent manner. Most notably, RecQL4 knockdown in metastatic prostate cancer cells drastically reduced their cell invasiveness in vitro and tumorigenicity in vivo demonstrating that RecQL4 is essential for prostate cancer promotion. Observation of a direct interaction of Rb and E2F1 proteins with RecQL4 promoter suggests that Rb-E2F1 pathway may regulate RecQL4 expression. Collectively, our study demonstrates that RecQL4 is an essential factor for prostate carcinogenesis.