Zhang Wenhua, Wang Jue, Chai Rong, Zhong Guangxin, Zhang Cong, Cao Wenjia, Yan Lei, Zhang Xiang, Xu Zhonghua
Department of Urology, Qilu Hospital of Shandong University, Jinan, People's Republic of China,
Central Laboratory, The Second Hospital of Shandong University, Jinan, People's Republic of China.
Onco Targets Ther. 2018 Aug 3;11:4537-4545. doi: 10.2147/OTT.S169155. eCollection 2018.
Long noncoding RNAs (lncRNAs) are proven to be key regulators in cancer biology. Our screening effort for clear cell renal cell carcinoma (ccRCC) prognosis-associated lncRNAs identified a novel lncRNA, ccRCC prognosis-associated transcript 4 (CRPAT4), as one of the top candidates that was previously uncharacterized. The aim of this study was to verify the clinical significance of CRPAT4 in ccRCC patients and to explore its biological role as well as the underlying mechanisms, in ccRCC cell lines.
Quantitative real-time polymerase chain reaction (PCR) was performed to demonstrate that CRPAT4 was differentially expressed between ccRCC and the normal controls and that high CRPAT4 expression significantly associated with advanced Fuhrman nuclear grades.
Kaplan-Meier survival analysis with The Cancer Genome Atlas KIRC RNA sequencing data indicated that high CRPAT4 expression was significantly associated with poor overall survival and progression-free survival. Functional studies indicated that CRPAT4 was an HIF-1α regulated gene, and CRPAT4 knockdown significantly inhibited cell migration and proliferation in the absence of HIF-1α. In addition, a mechanistic study revealed that CRPAT4 could regulate the expression of the migration-associated protein AVL9.
Collectively, our study first identified CRPAT4 as a hypoxia-regulated lncRNA, acting as an oncogene in ccRCC progression via regulating AVL9 protein, thus expanding our knowledge on the hypoxia pathway in ccRCC biology from a noncoding perspective. Moreover, CRPAT4 has the potential to be a prognostic marker in ccRCC patients.
长链非编码RNA（lncRNAs）已被证明是癌症生物学中的关键调节因子。我们对透明细胞肾细胞癌（ccRCC）预后相关lncRNAs的筛选工作确定了一种新型lncRNA，即ccRCC预后相关转录本4（CRPAT4），它是之前未被表征的顶级候选者之一。本研究的目的是验证CRPAT4在ccRCC患者中的临床意义，并探讨其在ccRCC细胞系中的生物学作用及其潜在机制。
采用定量实时聚合酶链反应（PCR）来证明CRPAT4在ccRCC与正常对照之间存在差异表达，且CRPAT4高表达与高级别Fuhrman核分级显著相关。
利用癌症基因组图谱KIRC RNA测序数据进行的Kaplan-Meier生存分析表明，CRPAT4高表达与较差的总生存期和无进展生存期显著相关。功能研究表明CRPAT4是一种受缺氧诱导因子-1α（HIF-1α）调控的基因，并且在缺乏HIF-1α的情况下，敲低CRPAT4可显著抑制细胞迁移和增殖。此外，机制研究揭示CRPAT4可调节迁移相关蛋白AVL9的表达。
总体而言，我们的研究首次确定CRPAT4是一种缺氧调节的lncRNA，它通过调节AVL9蛋白在ccRCC进展中发挥癌基因作用，从而从非编码角度扩展了我们对ccRCC生物学中缺氧途径的认识。此外，CRPAT4有可能成为ccRCC患者的预后标志物。
