rs2294008T下调抑癌基因PSCA促进膀胱癌演进的分子机制

Bladder cancer is the most common and the highest mortality of genitourinary malignancies,to find new theoretical method for genetic screening diagnosis and treatment is extremely important.Case reports have described that PSCA gene is a tumor suppressor for bladder cancer, rs2294008 is a missense single nucleotide polymorphism(SNP) located in the first exon of the PSCA gene, which may be the locus responsible for changes in the transcriptional activity of an upstream fragment of PSCA. The T allele of rs2294008 resulted in a significant reduction in transcriptional activity of the PSCA promoter. PSCA gene regulated INFα / β and CD59 to result in inhibition of cell proliferation and inducement of apoptosis in prostate cancer research.However, their mechanism of action of bladder cancer pathogenesis is not clear.This study was the determination of expression of PSCA mRNA,INFα/β and CD59 in bladder carcinoma tissue, adjacent to tumors,normal bladder tissue and bladder cancer cell lines,and the determination of PSCA rs2294008 genotype in bladder cancer and bladder cancer cell lines by PCR-RFLP. Through alteration of PSCA rs2294008 (C / T) polymorphism by LuciferaseAssay to regulate the activity of the PSCA gene, it will assess the association of rs2294008T with risk of bladder cancer and infer that PSCA rs2294008T may reduce the expression of PSCA mRNA and INFα /β and activate CD59. These results may indicate the possible mechanism of the PSCA gene in bladder cancer is that rs2294008T downregulates PSCA gene fragments and its downstream to result in the inducement of evolution of bladder cancer.The another objective of the study is toanalyze PSCA rs2294008T is associated with clinicopathology of bladder cancer, which may be an independent indicator of malignancy and prognosis in bladder cancer and may provide new ideas for the gene diagnosis and treatment.

膀胱癌是我国最常见，死亡率最高的泌尿生殖系恶性肿瘤。PSCA是膀胱癌抑癌基因，rs2294008T的SNPs可抑制PSCA基因转录活性，但它们的作用机理与膀胱癌的发病机制尚不明确。本研究拟通过测定膀胱癌、癌旁及正常膀胱组织和膀胱癌细胞株的PSCA mRNA及INFα/β、CD59的表达，并采用PCR-RFLP技术对膀胱癌及癌细胞株进行PSCA rs2294008基因型测定；通过荧光素酶报告基因实验改变癌细胞株基因型的同质异象（C?T），调控PSCA基因活性，研究其产物PSCA mRNA及INFα/β、CD59表达的变化，提出PSCA基因在膀胱癌中可能的机理：rs2294008T下调PSCA基因片段，致其PSCA mRNA表达降低及下游的INFα/β下降,CD5升高,最终促进膀胱癌演进；分析PSCA rs2294008T与膀胱癌临床及病理指标关系，探讨其可否为膀胱癌发生发展和预后的独立指标。

PSCA rs2294008C/T基因型与膀胱癌风险相关，其中PSCA rs2294008 T为膀胱癌易感基因型。PSCA rs2294008 T易感膀胱癌与其易下调PSCA m-RNA，减少IFNα/β和增加CD59的表达有关。PSCA rs2294008 T下调PSCA m-RNA的表达可能与rs2294008 T影响PSCA 5’上游端 -200+28bp区与转录因子的结合能力，降低PSCA启动子活性有关。研究结果部分揭示了rs2294008 T易感和促进膀胱癌的作用机理，对膀胱癌的风险评估有一定的指导和应用价值。