Peng Yurui, Xu Chenxin, Wen Jun, Zhang Yuanchuan, Wang Meng, Liu Xiaoxiao, Zhao Kang, Wang Zheng, Liu Yanjun, Zhang Tongtong
The Center of Gastrointestinal and Minimally Invasive Surgery, The Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, China.
Department of Colorectal Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Oncol. 2021 Aug 11;11:704038. doi: 10.3389/fonc.2021.704038. eCollection 2021.
Abnormal metabolism, including abnormal fatty acid metabolism, is an emerging hallmark of cancer. The current study sought to investigate the potential prognostic value of fatty acid metabolism-related long noncoding RNAs (lncRNAs) in colorectal cancer (CRC). To this end, we obtained the gene expression data and clinical data of patients with CRC from The Cancer Genome Atlas (TCGA) database. Through gene set variation analysis (GSVA), we found that the fatty acid metabolism pathway was related to the clinical stage and prognosis of patients with CRC. After screening differentially expressed RNAs, we constructed a fatty acid metabolism-related competing endogenous RNA (ceRNA) network based on the miRTarBase, miRDB, TargetScan, and StarBase databases. Next, eight fatty acid metabolism-related lncRNAs included in the ceRNA network were identified to build a prognostic signature with Cox and least absolute shrinkage and selection operator (LASSO) regression analyses, and a nomogram was established based on the lncRNA signature and clinical variables. The signature and nomogram were further validated by Kaplan-Meier survival analysis, Cox regression analysis, calibration plots, receiver operating characteristic (ROC) curves, decision curve analysis (DCA). Besides, the TCGA internal and the quantitative real-time polymerase chain reaction (qRT-PCR) external cohorts were applied to successfully validate the robustness of the signature and nomogram. Finally, assays showed that knockdown of prognostic lncRNA TSPEAR-AS2 decreased the triglyceride (TG) content and the expressions of fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1) in CRC cells, which indicated the important role of lncRNA TSPEAR-AS2 in modulating fatty acid metabolism of CRC. The result of Oil Red O staining showed that the lipid content in lncRNA TSPEAR-AS2 high expression group was higher than that in lncRNA TSPEAR-AS2 low expression group. Our study may provide helpful information for fatty acid metabolism targeting therapies in CRC.
异常代谢，包括异常脂肪酸代谢，是癌症新出现的一个标志。本研究旨在探究脂肪酸代谢相关长链非编码RNA（lncRNA）在结直肠癌（CRC）中的潜在预后价值。为此，我们从癌症基因组图谱（TCGA）数据库获取了CRC患者的基因表达数据和临床数据。通过基因集变异分析（GSVA），我们发现脂肪酸代谢途径与CRC患者的临床分期及预后相关。在筛选差异表达RNA后，我们基于miRTarBase、miRDB、TargetScan和StarBase数据库构建了一个脂肪酸代谢相关的竞争性内源RNA（ceRNA）网络。接下来，鉴定了ceRNA网络中包含的8个脂肪酸代谢相关lncRNA，通过Cox回归分析和最小绝对收缩与选择算子（LASSO）回归分析构建预后特征，并基于lncRNA特征和临床变量建立列线图。通过Kaplan-Meier生存分析、Cox回归分析、校准图、受试者工作特征（ROC）曲线、决策曲线分析（DCA）进一步验证了该特征和列线图。此外，应用TCGA内部队列和定量实时聚合酶链反应（qRT-PCR）外部队列成功验证了该特征和列线图的稳健性。最后，实验表明，敲低预后lncRNA TSPEAR-AS2可降低CRC细胞中的甘油三酯（TG）含量以及脂肪酸合酶（FASN）和乙酰辅酶A羧化酶1（ACC1）的表达，这表明lncRNA TSPEAR-AS2在调节CRC脂肪酸代谢中起重要作用。油红O染色结果显示，lncRNA TSPEAR-AS2高表达组的脂质含量高于lncRNA TSPEAR-AS2低表达组。我们的研究可能为CRC的脂肪酸代谢靶向治疗提供有用信息。
