Huang Shengquan, Liu Qian, Liao Qianjin, Wu Qingjian, Sun Bishao, Yang Zhenxing, Hu Xiaoyan, Tan Mingjia, Li Longkun
Department of Urology, Second Affiliated Hospital, Third Military Medical University, Chongqing, China.
Urological Center, Third Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Cancer Sci. 2018 Mar;109(3):678-687. doi: 10.1111/cas.13493. Epub 2018 Feb 20.
Prostate cancer can progress from androgen dependence to androgen deprivation resistance with some unknown mechanisms. The current study aims to explore the possible role of pituitary tumor transforming gene1 (PTTG1) in castration-resistant prostate cancer (CRPC). Initially, we found that PTTG1 expression was significantly increased in androgen-independent prostate cancer cell lines PC3, DU145 and CRPC specimens compared with that in androgen-dependent prostate cancer cell line LNCaP and initial prostate cancer specimens. PTTG1 overexpression significantly enhanced the cell survival rate, clonality and tumorigenicity in LNCaP cells upon androgen-deprivation therapy (ADT). While knockdown of PTTG1 expression significantly elevated the sensitivity of DU145 cells to ADT. The effects of PTTG1 overexpression on LNCaP cells may be ascribed to the induced EMT and increased CD44 CD24 cancer stem cell population. Furthermore, we detected that PTTG1 expression was regulated by interleukin-6 via activated signal transducer and activator of transcription 3 (STAT3) directly binding to the region -500 to +1 of PTTG1 promoter in LNCaP cells. In conclusion, our results elucidate that interleukin-6/STAT3 activation can increase PTTG1 expression and, consequently, promote the resistance to ADT in CRPC by inducing EMT and increasing the cancer stem cell population, suggesting that PTTG1 may be a novel therapeutic target for CRPC.
前列腺癌可从雄激素依赖发展为雄激素剥夺抵抗，其机制尚不清楚。本研究旨在探讨垂体肿瘤转化基因1（PTTG1）在去势抵抗性前列腺癌（CRPC）中的可能作用。最初，我们发现与雄激素依赖的前列腺癌细胞系LNCaP和原发性前列腺癌标本相比，PTTG1在雄激素非依赖性前列腺癌细胞系PC3、DU145及CRPC标本中的表达显著增加。在雄激素剥夺治疗（ADT）后，PTTG1过表达显著提高了LNCaP细胞的存活率、克隆性和致瘤性。而敲低PTTG1表达则显著提高了DU145细胞对ADT的敏感性。PTTG1过表达对LNCaP细胞的影响可能归因于诱导上皮-间质转化（EMT）和增加CD44⁺CD24⁻癌干细胞群体。此外，我们检测到在LNCaP细胞中，白细胞介素-6通过激活信号转导子和转录激活子3（STAT3）直接结合到PTTG1启动子的-500至+1区域来调节PTTG1表达。总之，我们的结果表明，白细胞介素-6/STAT3激活可增加PTTG1表达，从而通过诱导EMT和增加癌干细胞群体促进CRPC对ADT的抵抗，提示PTTG1可能是CRPC的一个新的治疗靶点。
