AP4 modulated by the PI3K/AKT pathway promotes prostate cancer proliferation and metastasis of prostate cancer via upregulating L-plastin.
AP4 modulated by the PI3K/AKT pathway promotes prostate cancer proliferation and metastasis of prostate cancer via upregulating L-plastin.
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PI3K/AKT通路调节的AP4通过上调L-plastin促进前列腺癌增殖和转移
DOI：
10.1038/cddis.2017.437
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发表时间：
2017-10-05
影响因子：
9
通讯作者：
Lin T
中科院分区：
文献类型：
--
作者：
Chen C;Cai Q;He W;Lam TB;Lin J;Zhao Y;Chen X;Gu P;Huang H;Xue M;Liu H;Su F;Huang J;Zheng J;Lin T
从雄激素依赖型到转移性去势抵抗性前列腺癌（PCa）的转变是分子病因学不确定的致命事件。我们之前的研究表明，L-plastin 参与 PCa 侵袭和转移，并且在激素依赖性 PCa 细胞系 LNCaP 中被雄激素和雌激素上调。我们最近发现，即使在雄激素剥夺后，L-plastin 表达也持续激活，这表明雄激素非依赖性转录因子可能调节其表达。在此，我们对 L-plastin 启动子进行了连续删除和荧光素酶分析，发现一个不依赖于雄激素的调节因子显着位于靠近转录起始位点（− 216 至+ 118）的区域，可能促进 L-plastin 上调。然后，如 EMSA、supershift 测定和 CHIP-qPCR 实验所证实，AP4 被鉴定为直接与 L-plastin 启动子结合的相关转录激活剂。此外，我们确定 AP4/L-plastin 轴受磷脂酰肌醇 3-激酶 (PI3K)/AKT 通路调节，有助于 PCa 转移和去势抵抗。此外，我们发现 AP4 通过在体外和体内上调 L-plastin 表达来促进 PCa 转移。我们收集了2005年至2015年在中山纪念医院接受前列腺切除术的患者的136例PCa组织和相应的邻近正常组织，并通过免疫组化法测定了AP4和L-plastin蛋白水平。结果显示，AP4水平与其下游靶基因L-plastin强相关，在PCa组织中显着上调，与淋巴结转移和Gleason评分>7呈正相关，是患者生存的独立预后因素。总之，这些发现支持了人 PCa 中 AP4/L-plastin 轴受 PI3K/AKT 通路调节的合理机制，并且可能代表 PCa 治疗中的新治疗靶点。
The transition from androgen-dependent to metastatic castration-resistant prostate cancer (PCa) is a lethal event of uncertain molecular aetiology. Our previous studies demonstrated that L-plastin is involved in PCa invasion and metastasis and is upregulated by androgen and oestrogen in the hormone-dependent PCa cell line LNCaP. We recently found that L-plastin expression is consistently activated even after androgen deprivation, suggesting that androgen-independent transcription factors may regulate its expression. Herein, we performed sequential deletion and luciferase analysis of the L-plastin promoter and found that an androgen-independent regulatory factor prominently located in the region close to the transcription initiation site (− 216 to+ 118) may facilitate L-plastin upregulation. AP4 was then identified as the relevant transcription activator that directly binds to the L-plastin promoter, as confirmed by EMSAs, supershift assays and CHIP-qPCR experiments. Moreover, we determined that the AP4/L-plastin axis is regulated by the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, contributing to PCa metastasis and castration resistance. Furthermore, we found that AP4 promotes PCa metastasis by upregulating L-plastin expression in vitro and in vivo. We collected a total of 136 PCa tissues and corresponding adjacent normal tissues from patients who underwent prostatectomy at Sun Yat-Sen Memorial Hospital from 2005 to 2015 and measured AP4 and L-plastin protein levels by immunohistochemistry. The results showed that AP4 levels strongly correlated with those of its downstream target gene L-plastin, were significantly upregulated in PCa tissues, were positively correlated with lymph node metastasis and Gleason scores over 7, and were an independent prognostic factor for patient survival. In summary, these findings support a plausible mechanism by which the AP4/L-plastin axis is regulated by the PI3K/AKT pathway in human PCa and may represent a novel therapeutic target in PCa treatment.
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影响因子：
11.2
作者：
Benitez A;Yates TJ;Lopez LE;Cerwinka WH;Bakkar A;Lokeshwar VB
通讯作者：
Lokeshwar VB
影响因子：
6.9
作者：
Horvath, Zsolt;Kovalszky, Ilona;Fullar, Alexandra;Kiss, Katalin;Schaff, Zsuzsa;Iozzo, Renato V.;Baghy, Kornelia
通讯作者：
Baghy, Kornelia
影响因子：
23.4
作者：
Marques, Rute B.;Aghai, Ashraf;van Weerden, Wytske M.
通讯作者：
van Weerden, Wytske M.
影响因子：
50.3
作者：
Carver BS;Chapinski C;Wongvipat J;Hieronymus H;Chen Y;Chandarlapaty S;Arora VK;Le C;Koutcher J;Scher H;Scardino PT;Rosen N;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
64.8
作者：
Karki R;Man SM;Malireddi RKS;Kesavardhana S;Zhu Q;Burton AR;Sharma BR;Qi X;Pelletier S;Vogel P;Rosenstiel P;Kanneganti TD
通讯作者：
Kanneganti TD