Department of General Practice, The First Hospital, China Medical University, Shenyang, China.
Department of Psychology, The First Hospital, China Medical University, Shenyang, China.
Cancer Med. 2018 Dec;7(12):6219-6233. doi: 10.1002/cam4.1854. Epub 2018 Oct 30.
The current prognostic long noncoding RNA (lncRNA) signatures for hepatocellular carcinoma (HCC) are still controversial and need to be optimized by systematic bioinformatics analyses with suitable methods and appropriate patients. Therefore, we performed the study to establish a credible lncRNA signature for HCC outcome prediction and explore the related mechanisms. Based on the lncRNA profile and the clinical data of carefully selected HCC patients (n = 164) in TCGA, six of 12727 lncRNAs, MIR22HG, CTC-297N7.9, CTD-2139B15.2, RP11-589N15.2, RP11-343N15.5, and RP11-479G22.8 were identified as the independent predictors of patients' overall survival in HCC by sequential univariate Cox and 1000 times Cox LASSO regression with 10-fold CV, and multivariate Cox analysis with 1000 times bootstrapping. In the Kaplan-Meier analysis with patients trichotomized by the six-lncRNA signature, high-risk patients showed significantly shorter survival than mid- and low-risk patients (log-rank test P < 0.0001). According to the ROCs, the six-lncRNA signature showed superior predictive capacity than the two existing four-lncRNA combinations and the traditional prognostic clinicopathological parameter TNM stage. Furthermore, low MIR22HG and CTC-297N7.9, but high CTD-2139B15.2, RP11-589N15.2, RP11-343N15.5, and RP11-479G22.8, were, respectively, demonstrated to be related with the malignant phenotypes of HCC. Functionally, the six lncRNAs were disclosed to involve in the regulation of multiple cell cycle and stress response-related pathways via mediating transcription regulation and chromatin modification. In conclusion, our study identified a novel six-lncRNA signature for resectable HCC prognosis prediction and indicated the underlying mechanisms of HCC progression and the potential functions of the six lncRNAs awaiting further elucidation.
当前用于肝细胞癌 (HCC) 的预后长非编码 RNA (lncRNA) 标志物仍存在争议，需要通过系统的生物信息学分析，使用合适的方法和合适的患者进行优化。因此，我们进行了这项研究，旨在建立一个可靠的 HCC 预后预测 lncRNA 标志物，并探索相关机制。基于 TCGA 中精心挑选的 HCC 患者（n=164）的 lncRNA 图谱和临床数据，通过序贯单因素 Cox 和 1000 次 Cox LASSO 回归（10 倍交叉验证）以及 1000 次 bootstrapping 的多因素 Cox 分析，从 12727 个 lncRNA 中鉴定出 6 个独立预测 HCC 患者总生存的 lncRNA，即 MIR22HG、CTC-297N7.9、CTD-2139B15.2、RP11-589N15.2、RP11-343N15.5 和 RP11-479G22.8。在根据这 6 个 lncRNA 标志物将患者分为三组的 Kaplan-Meier 分析中，高风险患者的生存明显短于中风险和低风险患者（对数秩检验 P<0.0001）。根据 ROCs，该六-lncRNA 标志物的预测能力优于现有的两个四-lncRNA 组合和传统的预后临床病理参数 TNM 分期。此外，低水平的 MIR22HG 和 CTC-297N7.9，而高水平的 CTD-2139B15.2、RP11-589N15.2、RP11-343N15.5 和 RP11-479G22.8，分别被证明与 HCC 的恶性表型相关。功能上，这 6 个 lncRNA 被揭示通过介导转录调控和染色质修饰参与多个细胞周期和应激反应相关通路的调控。总之，我们的研究确定了一个新的六-lncRNA 标志物，用于可切除 HCC 的预后预测，并指出了 HCC 进展的潜在机制和这 6 个 lncRNA 的潜在功能，有待进一步阐明。
