Novel lincRNA SLINKY is a prognostic biomarker in kidney cancer

• DOI: 10.18632/oncotarget.15703
• Publication Date: 2017-02-27T00:42:15Z
• Authors: Xue Gong; Zurab Siprashvili; Okyaz Eminaga; Zhewei Shen; Yusuke Sato; Haruki Kume; Yukio Homma; Seishi Ogawa; Paul A. Khavari; Jonathan R. Pollack; James D. Brooks
• Keywords: Adult; Male; 0303 health sciences; Protein Array Analysis; Kaplan-Meier Estimate; Middle Aged; Flow Cytometry; Prognosis; Disease-Free Survival; Kidney Neoplasms; 3. Good health; Gene Expression Regulation, Neoplastic; Heterogeneous-Nuclear Ribonucleoprotein K; 03 medical and health sciences; Area Under Curve; Biomarkers, Tumor; Humans; Immunoprecipitation; Female; Carcinoma, Renal Cell; Priority Research Paper; Aged; Cell Proliferation; Proportional Hazards Models

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.