The Arkadia-ESRP2 axis suppresses tumor progression: analyses in clear-cell renal cell carcinoma.
The Arkadia-ESRP2 axis suppresses tumor progression: analyses in clear-cell renal cell carcinoma.
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DOI：
10.1038/onc.2015.412
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发表时间：
2016-07-07
期刊：
影响因子：
8
通讯作者：
Miyazono K
中科院分区：
文献类型：
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作者：
Mizutani A;Koinuma D;Seimiya H;Miyazono K
肿瘤特异性选择性剪接与癌症的进展有关，包括透明细胞肾细胞癌（ccRCC）。使用癌症基因组图谱中的 ccRCC RNA 测序数据，我们发现上皮剪接调节蛋白 2 (ESRP2)（上皮细胞选择性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 靶外显子的表达与良好预后以及 ccRCC 中 Arkadia（也称为 RNF111）的表达相关。 Arkadia 与 ESRP2 发生物理相互作用，诱导多泛素化并调节其剪接功能。 Arkadia 和 ESRP2 以协调的方式抑制 ccRCC 肿瘤的生长。 Arkadia 的较低表达与 ccRCC 患者的晚期肿瘤分期和不良预后相关。因此，这项研究揭示了 Arkadia-ESRP2 轴在 ccRCC 中的新型肿瘤抑制作用。
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.