Sun Mianen, Tong Pan, Kong Wen, Dong Baijun, Huang Yiran, Park In Young, Zhou Lijun, Liu Xian-De, Ding Zhiyong, Zhang Xuesong, Bai Shanshan, German Peter, Powell Reid, Wang Quan, Tong Xuefei, Tannir Nizar M, Matin Surena F, Rathmell W Kimryn, Fuller Gregory N, McCutcheon Ian E, Walker Cheryl L, Wang Jing, Jonasch Eric
Department of Genitourinary Medical Oncology, University of Texas at MD Anderson Cancer Center, Houston, Texas.
Department of Bioinformatics and Computational Biology, University of Texas at MD Anderson Cancer Center, Houston, Texas.
Cancer Res. 2017 Oct 1;77(19):5313-5326. doi: 10.1158/0008-5472.CAN-17-0986. Epub 2017 Aug 14.
Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of loss is unique to ChRCC. We also observed a strong correlation between reduced expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of , , and genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed mutations in 33% of ChRCC where expression was repressed. In clinical specimens, combining loss with mutation produced an association with poor patient prognosis. In cells, combining loss and mutation increased cell proliferation and aneuploidy. Our results show how loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of and may enhance cellular survival and confer an aggressive phenotype in ChRCC. .
嫌色性肾细胞癌（ChRCC）的特征是染色体拷贝数（CN）发生重大变化。目前尚无模型可精确阐明这种肿瘤类型的分子驱动因素。肝细胞核因子1β（HNF1B）是基因表达的主要调节因子。在此，我们报告转录因子HNF1B在大多数ChRCC中表达下调，且其缺失程度在ChRCC中是独特的。我们还观察到ChRCC患者中HNF1B表达降低与非整倍体之间存在强烈相关性。在小鼠胚胎成纤维细胞或ACHN细胞中，HNF1B缺陷降低了纺锤体检查点蛋白MAD2L1和BUB1B以及细胞周期检查点蛋白RB1和p27的表达。此外，它改变了某些基因的染色质可及性并引发非整倍体发育。对癌症基因组图谱数据库的分析显示，在33%的HNF1B表达受抑制的ChRCC中存在HNF1B突变。在临床标本中，HNF1B缺失与HNF1B突变相结合与患者预后不良相关。在细胞中，HNF1B缺失与HNF1B突变相结合会增加细胞增殖和非整倍体。我们的结果表明HNF1B缺失如何导致有丝分裂蛋白调节异常和非整倍体的诱导。我们提出HNF1B和某些其他因素的协同缺失可能会增强细胞存活并赋予ChRCC侵袭性表型。
