Cackowski Frank C, Eber Matthew R, Rhee James, Decker Ann M, Yumoto Kenji, Berry Janice E, Lee Eunsohl, Shiozawa Yusuke, Jung Younghun, Aguirre-Ghiso Julio A, Taichman Russell S
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan.
Division of Hematology and Oncology, Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan.
J Cell Biochem. 2017 Apr;118(4):891-902. doi: 10.1002/jcb.25768. Epub 2016 Nov 10.
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, knockdown 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 PCa dormancy escape through a MAP kinase dependent mechanism, also involving p27, pluripotency transcription factors, and histone methylation. J. Cell. Biochem. 118: 891-902, 2017. © 2016 Wiley Periodicals, Inc.
许多前列腺癌（PCa）复发被认为是由于播散肿瘤细胞（DTCs）的重新激活所致。我们之前发现受体酪氨酸激酶TYRO3、AXL和MERTK的TAM家族在PCa休眠调节中发挥作用。然而，单个TAM受体的机制和作用在很大程度上尚不清楚。在PCa细胞中通过短发夹RNA（shRNA）敲低MERTK，但不敲低AXL或TYRO3，会导致P-Erk1/2与P-p38的比值降低、p27、NR2F1、SOX2和NANOG的表达增加、组蛋白H3K9me3和H3K27me3水平升高，并诱导G1/G0期阻滞，所有这些都与休眠相关。使用小干扰RNA（siRNA）也观察到了类似的效果。最重要的是，在心脏内注射小鼠异种移植模型中，PCa细胞中MERTK的敲低增加了无转移生存期。MERTK敲低在体外也未能抑制PCa生长，在体内也未能抑制皮下生长，这表明MERTK对休眠调节具有特异性，或者需要来自PCa微环境的信号。p38抑制剂SB203580可逆转MERTK对细胞周期和组蛋白甲基化的影响，这表明丝裂原活化蛋白激酶（MAP激酶）对MERTK休眠调节很重要。总体而言，本研究表明MERTK通过依赖MAP激酶的机制刺激PCa休眠逃逸，该机制还涉及p27、多能性转录因子和组蛋白甲基化。《细胞生物化学杂志》118: 891 - 902, 2017。© 2016威利期刊公司
