Lin Shin-Jen, Yang Dong-Rong, Wang Nancy, Jiang Ming, Miyamoto Hiroshi, Li Gonghui, Chang Chawnshang
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA.
Department of Urologic Surgery, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Oncoscience. 2015 Feb 9;2(2):142-50. doi: 10.18632/oncoscience.121. eCollection 2015.
A recent report indicated that the TR4 nuclear receptor might suppress the prostate cancer (PCa) initiation via modulating the DNA damage/repair system. Knocking-out peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that shares similar ligands/activators with TR4, promoted PCa initiation. Here we found 9% of PCa patients have one allele of PPARG deletion. Results from in vitro cell lines and in vivo mouse model indicated that during PCa initiation TR4 roles might switch from suppressor to enhancer in prostate cells when PPARG was deleted or suppressed (by antagonist GW9662). Mechanism dissection found targeting TR4 in the absence of PPARG might alter the stem cell population and epithelial-mesenchymal transition (EMT) signals. Together, these results suggest that whether TR4 can enhance or suppress PCa initiation may depend on the availability of PPARG and future potential therapy via targeting PPARG to battle PPARG-related diseases may need to consider the potential side effects of TR4 switched roles during the PCa initiation.
最近的一份报告表明，TR4核受体可能通过调节DNA损伤/修复系统来抑制前列腺癌（PCa）的起始。敲除过氧化物酶体增殖物激活受体γ（PPARG），一种与TR4共享相似配体/激活剂的核受体，会促进PCa的起始。我们发现9%的PCa患者有一个PPARG缺失等位基因。体外细胞系和体内小鼠模型的结果表明，在PCa起始过程中，当PPARG被缺失或抑制（通过拮抗剂GW9662）时，TR4在前列腺细胞中的作用可能从抑制因子转变为增强因子。机制剖析发现，在没有PPARG的情况下靶向TR4可能会改变干细胞群体和上皮-间质转化（EMT）信号。总之，这些结果表明，TR4是增强还是抑制PCa起始可能取决于PPARG的可用性，并且未来通过靶向PPARG对抗PPARG相关疾病的潜在疗法可能需要考虑在PCa起始过程中TR4角色转换的潜在副作用。
