PSCA对前列腺癌细胞自分泌IL-6的调控作用及其机制

The overexpression of prostate stem cell antigen (PSCA) was associated with the malignant proliferation and progression in human prostate cancer. Our prior data showed that human prostate cancer PC-3M cells had significantly reduced growth and invasive ability when PSCA gene was targetedly silenced by RNA interference, and that this procession was followed by the significantly lowered interleukin-6 (IL-6) levels autocrined by cancer cells. It is well-known that transcriptional control at the promoter of IL-6 gene is a major component regulating IL-6 expression levels, in which NF-κB is a key transcriptional activator. RAS/RAC-1/p38/ERK-1/2 signal transduction pathway as upstream effectors has an important role in the activation of NF-κB. Thus, we infer that PSCA expression may induce autocrine IL-6 in prostate cancer cells by activating NF-κB through the RAS/RAC-1/p38/ERK-1/2 pathway. On the platform of over-expressed and silenced PSCA human prostate cancer models in vitro and in vivo established by our previous work, the present study is to investigate the effects of PSCA expression on autocrine IL-6, RAS/RAC-1/p38/ERK-1/2 and its downstream NF-κB, and transcriptional activity of IL-6 gene promoter in prostate cancer cells, further to elucidate the mechanisms of PSCA gene regulating autocrine IL-6 in prostate cancer cells. The goal of this study is to provide the novel strategies for treatment of human prostate cancer.

PSCA过表达与前列腺癌恶性生长和进展密切相关。本课题组的前期研究发现：RNA干扰沉默PSCA基因的人前列腺癌PC-3M细胞生长及体外侵袭能力显著降低，同时伴有IL-6分泌水平的显著下降。已知IL-6表达主要由IL-6基因启动子在转录水平调控，而NF-κB是其关键的转录活化因子。RAS/RAC-1/p38/ERK-1/2信号转导通路作为上游效应基因在NF-κB的活化过程中具有重要作用。据此我们首次提出：PSCA表达可能通过以上信号流激活NF-κB，诱导前列腺癌细胞自分泌IL-6。本项目拟以体内、外高表达PSCA和沉默PSCA基因的人前列腺癌模型为平台，研究PSCA基因表达对癌细胞自分泌IL-6能力、RAS/RAC-1/p38/ERK-1/2通路及其下游NF-κB和IL-6基因启动子转录活性的影响，阐明PSCA对人前列腺癌细胞自分泌IL-6的调控作用及其机制，为前列腺癌的治疗提供新的切入点。

课题组严格按照国家自然科学基金委批准的资助项目计划书的内容、任务及目标进行研究，项目总体进展顺利。已按期完成了⑴PSCA和IL-6在前列腺癌组织的表达及其与患者临床特点、生化复发和总体生存期之间关系的研究；⑵PSCA表达对前列腺癌细胞自分泌IL-6的影响：建立稳定上调表达PSCA的人前列腺癌PC3M-PSCA细胞和下调表达PSCA（敲除PSCA基因）的DU145-shPSCA细胞，进一步检测细胞增殖、周期分布、迁移和侵袭能力及其与自分泌IL-6水平的关系；⑶构建荷人前列腺癌SCID鼠皮下移植瘤模型和肺转移模型，并进一步检测肿瘤组织PSCA、IL-6的表达及其与肿瘤生长、侵袭、远处转移的关系；⑷在细胞和动物水平，研究了PSCA基因表达对p38/NF-κB/IL-6信号通路的影响。. 课题组首次在细胞和动物水平发现，PSCA基因表达通过上调p38/NF-κB信号通路诱导人前列腺癌细胞自分泌IL-6，进而促进前列腺癌的侵袭性生长和远处转移；通过下调PSCA表达和/或阻抑p38/NF-κB通路可显著抑制前列腺癌IL-6的表达及其生长和转移。临床研究进一步证实，在人前列腺癌组织PSCA与IL-6的表达水平成显著正相关，并能够预测前列腺癌患者的生化复发（P<0.001）和总体生存率（P=0.017）。研究结果不仅为进一步深入研究PSCA的生物学功能奠定了基础，而且为前列腺癌的精准治疗提供了新靶点。经检索，国内、外尚无类似报道。因此，研究结果具有一定的创新性和重要的科学、临床实际意义。本研究课题为全新探索性的工作，共发表SCI收录文章4篇，总影响因子逾15；获市级科技进步奖二等奖和省级科学技术奖三等奖各1项；培养博士研究生2名、硕士研究生4名。. 已达到项目研究的预期目标。