BORIS介导前列腺癌中RNA融合的分子机制研究

Prostate cancer is becoming a common disease causing serious health problems in China. The incidence rate had been rising steadily. Because of the lack of effective early diagnostic methods, 70% of the prostate cancer patients were diagnosed with local invasion or bone metastases in China. A successful therapy for prostate cancer depends heavily on recognition of property and mechanism of the presence and progression of the disease. Formerly, fusion chimeric products were thought to be produced exclusively by chromosomal translocation in cancer. Recently, the applicant reported that a chimeric SLC45A3-ELK4 RNA, generated in the absence of chromosomal rearrangement, promoted the progression of prostate cancer. The RNA fusion process is regulated by androgen and CCCTC binding factor(CTCF). However the regulation mechanism remains unknown. BORIS, the paralogue of CTCF is expressed aberrantly in prostate cancer. It potentially involved in the development and progression of prostate cancer. In this study, we plan to investigate the regulation of the chimeric RNA fusion by the expression and the sub-cellular location of BORIS firstly, then the progression of prostate cancer cells by the regulation of BORIS, and finally search for novel chimeric RNA in prostate cancer by BORIS over-expression combined with RNA-seq. Our study would provide new tools facilitating the diagnosis and therapy of prostate cancer.

前列腺癌的发病率在我国有逐年上升的趋势并已成为威胁我国居民健康的常见疾病之一。由于缺乏有效的早期诊断方法，我国70%的前列腺癌患者被确诊时有局部浸润或已发生骨转移。认识前列腺癌的特征和发生途径是前列腺癌防治的必要条件。传统观点认为，肿瘤细胞染色质重构是融合基因产物形成的主要机制。然而申请人前期研究发现SLC45A3与ELK4基因间RNA而非DNA的融合诱导前列腺癌细胞增殖。融合RNA的表达受雄激素和CCCTC结合因子(CTCF)调控，但其作用机制不详。CTCF的同源因子BORIS在前列腺癌中高表达，可能参与前列腺癌的发生及发展。本项目拟首先研究前列腺癌中BORIS的表达及亚细胞定位与融合RNA SLC45A3-ELK4表达间的关系，然后调查BORIS是否推进前列腺癌的发生和发展，最后结合转录组测序的方法探寻与BORIS表达相关的新融合RNA,为前列腺癌的诊断治疗寻找新途径。

前列腺癌的发病率在我国有逐年上升的趋势并已成为威胁我国居民健康的常见疾病之一。由于缺乏有效的早期诊断方法，我国70%的前列腺癌患者被确诊时有局部浸润或已发生骨转移。认识前列腺癌的特征和发生途径是前列腺癌防治的必要条件。传统观点认为，肿瘤细胞染色质重构是融合基因产物形成的主要机制。然而申请人前期研究发现SLC45A3与ELK4基因间RNA而非DNA的融合诱导前列腺癌细胞增殖。融合RNA的表达受雄激素和CCCTC结合因子(CTCF)调控，但其作用机制不详。CTCF的同源因子BORIS在前列腺癌中高表达，可能参与前列腺癌的发生及发展。本项目首先研究了BORIS的表达对融合RNA的调控作用，发现BORIS与雄激素受体（AR）相互作用促进融合RNA的表达，BORIS也可通过调控融合RNA的母基因的表达调控融合RNA，BORIS通过调控融合RNA的表达促进前列腺癌的发生和发展。结合转录组测序的方法本项目找到SCNN1A-TNFRSF1A等受BORIS调控的新融合RNA，SCNN1A-TNFRSF1A的表达干扰抑制前列腺癌细胞增殖。另外，本项目研究也发现BORIS定位在癌细胞的细胞质和细胞核中，细胞质定位的BORIS抑制癌细胞凋亡。本项目深入研究了癌症相关因子BORIS的功能和作用机制，提示BORIS作为潜在肿瘤标记物的可能，为今后以BORIS及其下游调控的融合RNA或凋亡通路为切入点进行癌症的诊断治疗提供新思路。