Polycomb Repressor Complex 1 Member, BMI1 Contributes to Urothelial Tumorigenesis through p16-Independent Mechanisms.
Polycomb Repressor Complex 1 Member, BMI1 Contributes to Urothelial Tumorigenesis through p16-Independent Mechanisms.
复制标题
DOI：
10.1016/j.tranon.2015.08.002
复制
发表时间：
2015-10
影响因子：
5
通讯作者：
Chapman EJ
中科院分区：
文献类型：
--
作者：
De Faveri LE;Hurst CD;Roulson JA;Wood H;Sanchez-Carbayo M;Knowles MA;Chapman EJ
尿路上皮癌（UC）导致显著的发病率，并且仍然是治疗费用最高的癌症，因为非肌肉浸润性膀胱癌（NMIBC）患者需要反复切除和终身监测。需要新的治疗和分层方法来改善NMIBC和肌肉浸润性膀胱癌的前景。我们研究了B淋巴瘤Mo-MLV插入区1（BMI 1）在UC中的表达和作用。实时定量聚合酶链反应和免疫组化发现，在大多数UC细胞系和原发性肿瘤中，BMI 1过表达。与以前的一些报告相反，在两个独立的肿瘤组中未观察到与肿瘤分期或分级的相关性。此外，在癌前膀胱病变中检测到BMI 1的上调，表明在肿瘤发生的早期起作用。BMI 1不位于UC中基因组扩增的共同区域内。CDKN 2A基因座（编码p16肿瘤抑制基因）在某些细胞环境中是BMI 1的转录靶点。在UC细胞系和原代组织中，未观察到BMI 1和p16表达之间的相关性。逆转录病毒介导的BMI 1过表达在体外使正常人尿路上皮细胞（NHUC）永生化，并与诱导端粒酶活性、绕过衰老和抑制分化相关。通过NHUC-BMI 1的表达微阵列分析确定BMI 1对基因表达的影响。基因表达谱的元核分析表明BMI 1对α4/β1整合素介导的粘附、细胞骨架重塑和CREB 1介导的转录具有下游效应。
Urothelial carcinoma (UC) causes significant morbidity and remains the most expensive cancer to treat because of the need for repeated resections and lifelong monitoring for patients with non–muscle-invasive bladder cancer (NMIBC). Novel therapeutics and stratification approaches are needed to improve the outlook for both NMIBC and muscle-invasive bladder cancer. We investigated the expression and effects of B Lymphoma Mo-MLV Insertion Region 1 (BMI1) in UC. BMI1 was found to be overexpressed in most UC cell lines and primary tumors by quantitative real-time polymerase chain reaction and immunohistochemistry. In contrast to some previous reports, no association with tumor stage or grade was observed in two independent tumor panels. Furthermore, upregulation of BMI1 was detected in premalignant bladder lesions, suggesting a role early in tumorigenesis. BMI1 is not located within a common region of genomic amplification in UC. The CDKN2A locus (which encodes the p16 tumor suppressor gene) is a transcriptional target of BMI1 in some cellular contexts. In UC cell lines and primary tissues, no correlation between BMI1 and p16 expression was observed. Retroviral-mediated overexpression of BMI1 immortalized normal human urothelial cells (NHUC) in vitro and was associated with induction of telomerase activity, bypass of senescence, and repression of differentiation. The effects of BMI1 on gene expression were identified by expression microarray analysis of NHUC-BMI1. Metacore analysis of the gene expression profile implicated downstream effects of BMI1 on α4/β1 integrin-mediated adhesion, cytoskeleton remodeling, and CREB1-mediated transcription.