Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy.
Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy.
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DOI：
10.1002/jcb.25768
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发表时间：
2017-04
影响因子：
4
通讯作者：
Taichman RS
中科院分区：
文献类型：
--
作者：
Cackowski FC;Eber MR;Rhee J;Decker AM;Yumoto K;Berry JE;Lee E;Shiozawa Y;Jung Y;Aguirre-Ghiso JA;Taichman RS
许多前列腺癌（PCa）复发被认为是由于播散性肿瘤细胞（DTC）的再活化。我们以前发现了TAM家族的受体酪氨酸激酶TYRO 3，AXL和MERTK在PCa休眠调节中的作用。然而，单个TAM受体的机制和贡献在很大程度上是未知的。在PCa细胞中，通过shRNA敲低MERTK而非AXL或TYRO 3可诱导P-Erk 1/2与P-p38的比率降低，p27、NR 2F 1、SOX 2和NANOG的表达增加，诱导组蛋白H3 K9 me 3和H3 K27 me 3水平升高，并诱导G1/G 0阻滞，所有这些均与休眠相关。用siRNA也观察到类似的效果。最重要的是，PCa细胞中MERTK的敲低增加了心脏内注射小鼠异种移植模型中的无转移存活。MERTK敲低也未能抑制体外PCa生长和体内皮下生长，这表明MERTK对休眠调节具有特异性或需要来自PCa微环境的信号。MERTK对细胞周期和组蛋白甲基化的影响被p38抑制剂SB 203580逆转，这表明MAP激酶在MERTK休眠调节中的重要性。总之，这项研究表明，MERTK刺激前列腺癌休眠逃逸通过MAP激酶依赖性机制，也涉及p27，多能性转录因子，和组蛋白甲基化。
Many prostate cancer (PCa) recurrences are thought to be due to reactivation of disseminated tumor cells (DTCs). We previously found a role of the TAM family of receptor tyrosine kinases TYRO3, AXL and MERTK in PCa dormancy regulation. However, the mechanism and contributions of the individual TAM receptors is largely unknown. Knockdown of MERTK, but not AXL or TYRO3 by shRNA in PCa cells induced a decreased ratio of P-Erk1/2 to P-p38, increased expression of p27, NR2F1, SOX2, and NANOG, induced higher levels of histone H3K9me3 and H3K27me3, and induced a G1/G0 arrest, all of which are associated with dormancy. Similar effects were also observed with siRNA. Most importantly, knock down of MERTK in PCa cells increased metastasis free survival in an intra-cardiac injection mouse xenograft model. MERTK knockdown also failed to inhibit PCa growth in vitro and subcutaneous growth in vivo, which suggests that MERTK has specificity for dormancy regulation or requires a signal from the PCa microenvironment. The effects of MERTK on the cell cycle and histone methylation were reversed by p38 inhibitor SB203580, which indicates the importance of MAP kinases for MERTK dormancy regulation. Overall, this study shows that MERTK stimulates prostate cancer dormancy escape through a MAP kinase dependent mechanism, also involving p27, pluripotency transcription factors, and histone methylation.