A Novel Autophagy-Related IncRNAs Signature for Prognostic Prediction and Clinical Value in Patients With Pancreatic Cancer.
A Novel Autophagy-Related IncRNAs Signature for Prognostic Prediction and Clinical Value in Patients With Pancreatic Cancer.
复制标题
DOI：
10.3389/fcell.2020.606817
复制
发表时间：
2020
影响因子：
5.5
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Deng Z;Li X;Shi Y;Lu Y;Yao W;Wang J
自噬是贯穿于肿瘤发生、发展的重要生物学过程。然而，自噬相关lncRNA在胰腺癌（PC）中的作用仍然不清楚。在这项研究中，我们确定了自噬相关的lncRNA（ARlncRNA），并将来自癌症基因组图谱的PC患者分为训练集和验证集。首先，我们在训练集中利用最小绝对收缩和选择算子惩罚的考克斯回归分析和多元考克斯回归分析构造签名。然后，我们通过生存分析、受试者操作特征分析和考克斯回归验证了训练集和验证集中风险特征的独立预后作用。建立诺模图以证明特征的预测能力。此外，高风险评分与不良结局和严重临床特征显著相关。免疫细胞浸润、肿瘤突变负荷和化疗靶分子表达水平的风险评分之间的Pearson分析表明，签名可以预测免疫治疗和靶向治疗的疗效。接下来，我们构建了一个lncRNA-miRNA-mRNA调控网络，并在连接图（CMap）中鉴定了几种潜在的小分子药物。此外，定量实时PCR（qRT-PCR）分析表明，血清LINC 01559可以作为诊断生物标志物。体外分析显示，LINC 01559的抑制抑制PC细胞增殖、迁移和侵袭。此外，沉默LINC 01559抑制吉西他滨诱导的自噬并促进PC细胞对吉西他滨的敏感性。总之，我们确定了一种新的ARlncRNA特征，其对于PC患者的可靠预后预测和个性化治疗具有有价值的临床实用性。抑制LINC 01559可能是克服耐药性的新策略。
Autophagy is an important bioprocess throughout the occurrence and development of cancer. However, the role of autophagy-related lncRNAs in pancreatic cancer (PC) remains obscure. In the study, we identified the autophagy-related lncRNAs (ARlncRNAs) and divided the PC patients from The Cancer Genome Atlas into training and validation set. Firstly, we constructed a signature in the training set by the least absolute shrinkage and selection operator penalized cox regression analysis and the multivariate cox regression analysis. Then, we validated the independent prognostic role of the risk signature in both training and validation set with survival analysis, receiver operating characteristic analysis, and Cox regression. The nomogram was established to demonstrate the predictive power of the signature. Moreover, high risk scores were significantly correlated to worse outcomes and severe clinical characteristics. The Pearson’s analysis between risk scores with immune cells infiltration, tumor mutation burden, and the expression level of chemotherapy target molecules indicated that the signature could predict efficacy of immunotherapy and targeted therapy. Next, we constructed an lncRNA–miRNA–mRNA regulatory network and identified several potential small molecule drugs in the Connectivity Map (CMap). What’s more, quantitative real-time PCR (qRT-PCR) analysis showed that serum LINC01559 could serve as a diagnostic biomarker. In vitro analysis showed inhibition of LINC01559 suppressed PC cell proliferation, migration, and invasion. Additionally, silencing LINC01559 suppressed gemcitabine-induced autophagy and promoted the sensitivity of PC cells to gemcitabine. In conclusion, we identified a novel ARlncRNAs signature with valuable clinical utility for reliable prognostic prediction and personalized treatment of PC patients. And inhibition of LINC01559 might be a novel strategy to overcome chemoresistance.