Novel lincRNA SLINKY is a prognostic biomarker in kidney cancer.
Novel lincRNA SLINKY is a prognostic biomarker in kidney cancer.
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DOI：
10.18632/oncotarget.15703
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发表时间：
2017-03-21
期刊：
影响因子：
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通讯作者：
Brooks JD
中科院分区：
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作者：
Gong X;Siprashvili Z;Eminaga O;Shen Z;Sato Y;Kume H;Homma Y;Ogawa S;Khavari PA;Pollack JR;Brooks JD
透明细胞肾细胞癌（ccRCC）显示出广泛的临床行为，需要预后生物标志物对患者进行分层以进行适当的管理。我们试图确定长基因间非编码RNA（lincRNA）是否可以预测患者的生存。通过挖掘癌症基因组图谱（TCGA）转录组（RNA-seq）数据，对466例ccRCC病例（随机分为发现和验证组）注释约21，000个lncRNA，鉴定候选预后lincRNA。先前未表征的lincRNA，SLINKY（肾癌中的存活预测LINcRNA），是排名最高的预后lincRNA，并在独立的东京大学队列中得到验证（P=0.004）。在多变量分析中，SLINKY表达预测总生存期与肿瘤分期和分级无关[TCGA HR=3.5（CI，2.2-5.7），P < 0.001; Tokyo HR=8.4（CI，1.8-40.2），P = 0.007]，并且通过决策树、ROC和决策曲线分析，增加了独立的预后价值。在ccRCC细胞系中，SLINKY敲低降低了癌细胞增殖（细胞周期G1停滞），并诱导了富含细胞增殖和存活过程的转录组变化。值得注意的是，细胞系中受SLINKY敲低影响的基因本身是预后性的，并且与ccRCC患者样品中的SLINKY表达相关。从结合伴侣的筛选中，我们鉴定了SLINKY与异质核核糖核蛋白K（HNRNPK）的直接结合，其敲除概括了SLINKY敲除表型。因此，SLINKY是ccRCC中的稳健预后生物标志物，其中它可能与HNRNPK一起在癌细胞增殖中起作用。
Clear cell renal cell carcinomas (ccRCC) show a broad range of clinical behavior, and prognostic biomarkers are needed to stratify patients for appropriate management. We sought to determine whether long intergenic non-coding RNAs (lincRNAs) might predict patient survival. Candidate prognostic lincRNAs were identified by mining The Cancer Genome Atlas (TCGA) transcriptome (RNA-seq) data on 466 ccRCC cases (randomized into discovery and validation sets) annotated for ~21,000 lncRNAs. A previously uncharacterized lincRNA, SLINKY (Survival-predictive LINcRNA in KidneY cancer), was the top-ranked prognostic lincRNA, and validated in an independent University of Tokyo cohort (P=0.004). In multivariable analysis, SLINKY expression predicted overall survival independent of tumor stage and grade [TCGA HR=3.5 (CI, 2.2-5.7), P < 0.001; Tokyo HR=8.4 (CI, 1.8-40.2), P = 0.007], and by decision tree, ROC and decision curve analysis, added independent prognostic value. In ccRCC cell lines, SLINKY knockdown reduced cancer cell proliferation (with cell-cycle G1 arrest) and induced transcriptome changes enriched for cell proliferation and survival processes. Notably, the genes affected by SLINKY knockdown in cell lines were themselves prognostic and correlated with SLINKY expression in the ccRCC patient samples. From a screen for binding partners, we identified direct binding of SLINKY to Heterogeneous Nuclear Ribonucleoprotein K (HNRNPK), whose knockdown recapitulated SLINKY knockdown phenotypes. Thus, SLINKY is a robust prognostic biomarker in ccRCC, where it functions possibly together with HNRNPK in cancer cell proliferation.