EphA3, induced by PC-1/PrLZ, contributes to the malignant progression of prostate cancer
EphA3, induced by PC-1/PrLZ, contributes to the malignant progression of prostate cancer
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PC-1/PrLZ 诱导的 EphA3 有助于前列腺癌的恶性进展。
DOI：
10.3892/or.2014.3482
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发表时间：
2014-12-01
期刊：
影响因子：
4.2
通讯作者：
Zhou, Jianguang
中科院分区：
文献类型：
--
作者：
Wu, Ruiqin;Wang, Hongtao;Zhou, Jianguang
我们先前的研究揭示了PC-1/PrLZ，一个新的分离的前列腺特异性基因，在体外和体内前列腺癌（PCa）的进展的潜在联系。为了进一步了解PC-1促进PCa表达的机制，利用基因芯片技术对PC-1诱导的差异基因进行了表达分析。在所有差异表达基因中，EphA 3的改变程度最大。EphA 3已被鉴定为与多种肿瘤进展相关。然而，关于EphA 3在PCa中的功能知之甚少。在本研究中，我们的目的是确定EphA 3是否由PC-1诱导和EphA 3在PCa中表达的功能意义。我们发现PC-1的过表达增加了EphA 3的量，并且PC-1的敲低导致PCa细胞中EphA 3的减少。使用细胞系在体外以及使用小鼠模型和临床样本在体内研究EphA 3促成PCa的功能意义和机制。结果表明EphA 3促进LNCaP细胞的增殖和存活，抑制EphA 3则抑制C4-2B细胞的存活。EphA 3增强了裸小鼠中LNCaP细胞的肿瘤发展。在临床PCa标本中鉴定了EphA 3水平与PCa的Gleason分级之间的正相关性。此外，细胞定位随着Gleason分级而改变。我们进一步检测到EphA 3增加Akt（Ser 473和Thr 308）的磷酸化，表明EphA 3激活Akt途径。总而言之，EphA 3是由PC-1诱导的，并促进了前列腺癌的恶性进展。我们的研究结果首次证明EphA 3是人类前列腺癌发展和进展的新启动子。
Our previous study revealed the potential linkage of PC-1/PrLZ, a novel isolated prostate-specific gene, to the progression of prostate cancer (PCa) in vitro and in vivo. To gain more insight into the mechanism of PC-1-induced promotion of PCa, expression analysis of differential genes induced by PC-1 was scanned by microarray. Among all the differentially expressed genes, EphA3 was altered to the greatest extent. EphA3 has been identified to be associated with multiple tumor progression. However, little is known concerning the function of EphA3 in PCa. In the present study, we aimed to ascertain whether EphA3 is induced by PC-1 and the functional significance of EphA3 expression in PCa. We found that overexpression of PC-1 increased the amount of EphA3 and that knockdown of PC-1 led to a decrease in EphA3 in PCa cells. The functional significance and mechanisms by which EphA3 contributes to PCa was investigated in vitro using cell lines, and in vivo using a mouse model and clinical specimens. The results showed that EphA3 enhanced the proliferation and survival of LNCaP cells and suppression of EphA3 inhibited the survival of C4-2B cells. EphA3 enhanced the tumor development of LNCaP cells in null mice. A positive correlation between the levels of EphA3 and the Gleason grade of PCa was identified in clinical PCa specimens. In addition, cellular localization changed with Gleason grade. We further detected that EphA3 increased phosphorylation of Akt (Ser473 and Thr308), indicating that EphA3 activated the Akt pathway. Taken together, EphA3 was induced by PC-1 and contributed to the malignant progression of prostate cancer. Our results provide the first demonstration that EphA3 is a novel promoter of human prostate cancer development and progression.