长链非编码RNA PANTR1与透明细胞肾细胞癌的不良预后相关，并影响其血管生成和细胞凋亡。
Long Non-Coding RNA PANTR1 is Associated with Poor Prognosis and Influences Angiogenesis and Apoptosis in Clear-Cell Renal Cell Cancer.
作者信息
Seles Maximilian, Hutterer Georg C, Foßelteder Johannes, Svoboda Marek, Resel Margit, Barth Dominik A, Pichler Renate, Bauernhofer Thomas, Zigeuner Richard E, Pummer Karl, Slaby Ondrej, Klec Christiane, Pichler Martin
机构信息
Department of Urology, Medical University of Graz, 8036 Graz, Austria.
Division of Oncology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
出版信息
Cancers (Basel). 2020 May 10;12(5):1200. doi: 10.3390/cancers12051200.
POU3F3 adjacent non-coding transcript 1 (PANTR1) is an oncogenic long non-coding RNA with significant influence on numerous cellular features in different types of cancer. No characterization of its role in renal cell carcinoma (RCC) is yet available. In this study, PANTR1 expression was confined to human brain and kidney tissue and was found significantly up-regulated in clear-cell renal cell carcinoma tissue (ccRCC) compared to non-cancerous kidney tissue in two independent cohorts ( < 0.001 for both cohorts). In uni- and multivariate Cox regression analysis, ccRCC patients with higher levels of PANTR1 showed significantly poorer disease-free survival in our own respective cohort ( = 175, hazard ratio: 4.3, 95% confidence interval: 1.45-12.75, = 0.008) in accordance with significantly poorer overall survival in a large The Cancer Genome Atlas database (TCGA) cohort ( = 530, hazard ratio: 2.19, 95% confidence interval: 1.59-3.03, ≤ 0.001). To study the underlying cellular mechanisms mediated by varying levels of PANTR1 in kidney cancer cells, we applied siRNA-mediated knock-down experiments in three independent ccRCC cell lines (RCC-FG, RCC-MF, 769-P). A decrease in PANTR1 levels led to significantly reduced cellular growth through activation of apoptosis in all tested cell lines. Moreover, as angiogenesis is a critical driver in ccRCC pathogenesis, we identified that PANTR1 expression is critical for in vitro tube formation and endothelial cell migration ( < 0.05). On the molecular level, knock-down of PANTR1 led to a decrease in Vascular Endothelial growth factor A (VEGF-A) and cell adhesion molecule laminin subunit gamma-2 (LAMC2) expression, corroborated by a positive correlation in RCC tissue (for VEGF-A = 0.19, < 0.0001, for LAMC2 = 0.13, = 0.0028). In conclusion, this study provides first evidence that PANTR1 has a relevant role in human RCC by influencing apoptosis and angiogenesis.
POU3F3相邻非编码转录本1（PANTR1）是一种致癌性长链非编码RNA，对不同类型癌症的众多细胞特征有显著影响。目前尚无关于其在肾细胞癌（RCC）中作用的相关描述。在本研究中，PANTR1表达局限于人类脑和肾组织，并且在两个独立队列中发现，与非癌性肾组织相比，其在透明细胞肾细胞癌组织（ccRCC）中显著上调（两个队列均P<0.001）。在单变量和多变量Cox回归分析中，PANTR1水平较高的ccRCC患者在我们各自的队列中显示出显著较差的无病生存期（n = 175，风险比：4.3，95%置信区间：1.45 - 12.75，P = 0.008），这与大型癌症基因组图谱数据库（TCGA）队列中显著较差的总生存期一致（n = 530，风险比：2.19，95%置信区间：1.59 - 3.03，P≤0.001）。为了研究肾癌细胞中不同水平的PANTR1介导的潜在细胞机制，我们在三个独立的ccRCC细胞系（RCC - FG、RCC - MF、769 - P）中进行了siRNA介导的敲低实验。PANTR1水平的降低通过激活所有测试细胞系中的凋亡导致细胞生长显著减少。此外，由于血管生成是ccRCC发病机制中的关键驱动因素，我们确定PANTR1表达对于体外血管生成和内皮细胞迁移至关重要（P<0.05）。在分子水平上，PANTR1的敲低导致血管内皮生长因子A（VEGF - A）和细胞粘附分子层粘连蛋白亚基γ - 2（LAMC2）表达降低，这在RCC组织中的正相关性得到了证实（对于VEGF - A，r = 0.19，P<0.0001，对于LAMC2，r = 0.13，P = 0.0028）。总之，本研究提供了首个证据，表明PANTR1通过影响凋亡和血管生成在人类RCC中发挥相关作用。
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