Mizutani A, Koinuma D, Seimiya H, Miyazono K
Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Division of Molecular Biotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Ariake, Koto-ku, Tokyo, Japan.
Oncogene. 2016 Jul 7;35(27):3514-23. doi: 10.1038/onc.2015.412. Epub 2015 Nov 2.
Tumor-specific alternative splicing is implicated in the progression of cancer, including clear-cell renal cell carcinoma (ccRCC). Using ccRCC RNA sequencing data from The Cancer Genome Atlas, we found that epithelial splicing regulatory protein 2 (ESRP2), one of the key regulators of alternative splicing in epithelial cells, is expressed in ccRCC. ESRP2 mRNA expression did not correlate with the overall survival rate of ccRCC patients, but the expression of some ESRP-target exons correlated with the good prognosis and with the expression of Arkadia (also known as RNF111) in ccRCC. Arkadia physically interacted with ESRP2, induced polyubiquitination and modulated its splicing function. Arkadia and ESRP2 suppressed ccRCC tumor growth in a coordinated manner. Lower expression of Arkadia correlated with advanced tumor stages and poor outcomes in ccRCC patients. This study thus reveals a novel tumor-suppressive role of the Arkadia-ESRP2 axis in ccRCC.
肿瘤特异性可变剪接与癌症进展有关，包括肾透明细胞癌（ccRCC）。利用来自癌症基因组图谱的ccRCC RNA测序数据，我们发现上皮剪接调节蛋白2（ESRP2），上皮细胞中可变剪接的关键调节因子之一，在ccRCC中表达。ESRP2 mRNA表达与ccRCC患者的总生存率无关，但一些ESRP靶向外显子的表达与ccRCC的良好预后以及Arkadia（也称为RNF111）的表达相关。Arkadia与ESRP2发生物理相互作用，诱导多聚泛素化并调节其剪接功能。Arkadia和ESRP2以协同方式抑制ccRCC肿瘤生长。Arkadia的低表达与ccRCC患者的晚期肿瘤阶段和不良预后相关。因此，本研究揭示了Arkadia - ESRP2轴在ccRCC中的一种新的肿瘤抑制作用。
