PLA2G7在前列腺癌中的表达和调控机制的研究

PLA2G7 (phospholipase A2 group VII) is commonly known as lipoprotein-associated phospholipase A2 (Lp-PLA2) or plasma platelet activating factor acetylhydrolase (PAF-AH). PLA2G7 is an important mediator of inflammation and lipid metabolism. Elevated serum levels of Lp-PLA2 have been associated with increased cardiovascular risk in healthy populations and in patients with known vascular disease. Recently PLA2G7 has been found associated with formation and progression of malignant tumor. We have found that the expression of PLA2G7 in malignant tumor was elevated than the adjacent benign tumor through the tissue microarray analysis in paraffin embedded tissue from radical prostatectomy. In addition, higher mRNA levels were detected in high graded tumors than low/mediate tumors in the fresh prostate tissues. Furthermore in the DNA microarray analysis, we found a close relationship between PLA2G7 expression and TMPRSS2/ERG positivity. Based on the literatures and our previous studies, we plan to carry out our research on three aspects. Firstly, we plan to study the effect of PLA2G7 on the proliferation, adhesion, invasion and apoptosis of tumor cells through RNAi technique. Secondly, due to the PLA2G7 was found to relate with inflammation. We plan to study the extent of inflammation of prostate cancer tissue and correspondent expression of PLA2G7.Also in the cell level we analysis the role of PLA2G7 in respond to the oxygen free radicals and anti-lipid drugs. Finally, due to the close relationship with the existence of TMPRSS2/ERG, we explore the mechanism of modulation of PLA2G7. We plan to prove that TMPRSS2/ERG could bind to the promoter of PLA2G7 and regulate its expression. Through the above research plan, we hope to provide new evidence involving the formation, progression of prostate cancer and find an alternative tool for the early diagnosis and individualized therapy.

PLA2G7是脂蛋白代谢和炎症反应通路中的重要因子，和心血管系统疾病的发生密切相关，近年来逐渐发现该因子和肿瘤的发生也有紧密相关。我们课题组在前期对前列腺癌手术的组织样本的研究发现，PLA2G7在前列腺癌肿瘤组织中的表达高于良性组织，且在高级别的肿瘤组织中表达更高。进一步研究发现PLA2G7的表达和TMPRSS2/ERG阳性的前列腺癌密切相关。本项目主要研究三个方面，PLA2G7和前列腺癌进展的关系，前列腺癌组织中PLA2G7表达和局部炎症反应的关系，PLA2G7和TMPRSS2/ERG相互影响和调控的关系。从而有可能在前列腺癌发病机制，分子分型方面提供新的依据，为临床诊断和个体化治疗发现新的可行途径。

PLA2G7是脂蛋白代谢和炎症反应通路中的重要因子，和心血管系统疾病的发生密切相关，近年来逐渐发现该因子和肿瘤的发生也有紧密相关。我们课题组在前期对前列腺癌手术的组织样本的研究发现，PLA2G7在前列腺癌肿瘤组织中的表达高于良性组织，且在高级别的肿瘤组织中表达更高。进一步研究发现PLA2G7的表达和TMPRSS2/ERG阳性的前列腺癌密切相关。本项目主要研究三个方面，PLA2G7和前列腺癌细胞增殖、浸润、凋亡的关系，前列腺癌组织中PLA2G7表达和局部炎症反应的关系，PLA2G7和TMPRSS2/ERG相互影响和调控的关系。研究结果：（1）PLA2G7在前列腺癌组织中阳性率明显高于癌旁良性前列腺组织，在前列腺癌细胞系中表达水平也明显高于前列腺正常细胞系，PLA2G7和肿瘤组织的分级有密切相关性，PLA2G7 mRNA水平随着Gleason评分增加而增高；（2）敲低CWR22Rv1和VCaP前列腺癌细胞中PLA2G7表达后，相较于对照组，细胞周期和增殖活性在两株细胞系中未有明显的改变，但细胞侵袭和迁移能力明显降低，表明PLA2G7的过度表达可以增加前列腺癌转移能力。我们利用western blot检测转染Si-PLA2G7前后前列腺癌细胞中EMT相关蛋白分子表达水平，发现较空白组合对照组，转染Si-PLA2G7组上皮标志蛋白E-Cadherin表达明显上调，而间质标志蛋白Vimetin和N-Cadherin表达明显下调从而有可能在前列腺癌发病机制，分子分型方面提供新的依据，为临床诊断和个体化治疗发现新的可行途径。