Song Er-Lin, Xing Li, Wang Liang, Song Wen-Ting, Li Dan-Bin, Wang Yi, Gu Yi-Wei, Liu Ming-Ming, Ni Wen-Jun, Zhang Peng, Ma Xin, Zhang Xu, Yao Jie, Chen Yang, An Rui-Hua
Department of Urinary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150007, Heilongjiang Province, P. R. China.
Department of Nephrology, The First Affiliated Hospital of Harbin Medical University, Harbin 150007, Heilongjiang Province, P. R. China.
Aging (Albany NY). 2019 Aug 10;11(15):5705-5725. doi: 10.18632/aging.102154.
Accumulating evidence reveals the principal role of long noncoding RNAs in the progression of clear cell renal cell carcinoma (ccRCC). However, little is known about the underlying mechanism of ADAM metallopeptidase with thrombospondin type 1 motif, 9 antisense RNA 2 (ADAMTS9-AS2) in ccRCC. Here, bioinformatics analyses verified ADAMTS9-AS2 is a long noncoding RNA and its high expression was associated with better prognosis of ccRCC. ADAMTS9-AS2 was clearly downregulated in ccRCC clinical samples and cell lines. Clinical data showed low-expressed ADAMTS9-AS2 was correlated with worse overall survival in ccRCC patients. Next, miR-27a-3p was identified as an inhibitory target of ADAMTS9-AS2 by dual-luciferase reporter and RNA immunoprecipitation assays. Both overexpressed ADAMTS9-AS2 and underexpressed miR-27a-3p in ccRCC cell lines led to the inhibition of cell proliferation and the reduction of chemoresistance. Additionally, Forkhead Box Protein O1 (FOXO1) was confirmed as the inhibitory target of miR-27a-3p. Induced by ADAMTS9-AS2 overexpression, cell proliferation and chemoresistance exhibited an obvious reduction, FOXO1 expression showed an evident increase, but all were reversed after miR-27a-3p was simultaneously overexpressed. Collectively, these results suggest ADAMTS9-AS2 inhibits the progression and impairs the chemoresistance of ccRCC via miR-27a-3p-mediated regulation of FOXO1 and may serve as a prognostic biomarker and therapeutic target for ccRCC.
越来越多的证据揭示了长链非编码RNA在透明细胞肾细胞癌（ccRCC）进展中的主要作用。然而，关于含血小板反应蛋白基序的金属蛋白酶9反义RNA2（ADAMTS9-AS2）在ccRCC中的潜在机制知之甚少。在此，生物信息学分析证实ADAMTS9-AS2是一种长链非编码RNA，其高表达与ccRCC的较好预后相关。ADAMTS9-AS2在ccRCC临床样本和细胞系中明显下调。临床数据显示，ccRCC患者中低表达的ADAMTS9-AS2与较差的总生存期相关。接下来，通过双荧光素酶报告基因和RNA免疫沉淀试验，鉴定出miR-27a-3p是ADAMTS9-AS2的抑制靶点。ccRCC细胞系中过表达ADAMTS9-AS2和低表达miR-27a-3p均导致细胞增殖受到抑制和化疗耐药性降低。此外，叉头框蛋白O1（FOXO1）被证实是miR-27a-3p的抑制靶点。ADAMTS9-AS2过表达诱导后，细胞增殖和化疗耐药性明显降低，FOXO1表达明显增加，但在miR-27a-3p同时过表达后，所有这些变化均被逆转。总体而言，这些结果表明ADAMTS9-AS2通过miR-27a-3p介导的FOXO1调节抑制ccRCC的进展并削弱其化疗耐药性，可能作为ccRCC的预后生物标志物和治疗靶点。
