Comprehensive analysis of lncRNA-mRNA co-expression networks in HPV-driven cervical cancer reveals the pivotal function of LINC00511-PGK1 in tumorigenesis
Comprehensive analysis of lncRNA-mRNA co-expression networks in HPV-driven cervical cancer reveals the pivotal function of LINC00511-PGK1 in tumorigenesis
复制标题
DOI：
10.1016/j.compbiomed.2023.106943
复制
发表时间：
2023-04
影响因子：
7.7
通讯作者：
Xu Xin;Jia-Yin Yu;Jun-Yang Huang;Wang Rui;Xiong-Ri Kuang;Long-Rui Dang;Jie Liu;Jue-Yu Zhou-Jue-Yu-Z
中科院分区：
文献类型：
--
作者：
Xu Xin;Jia-Yin Yu;Jun-Yang Huang;Wang Rui;Xiong-Ri Kuang;Long-Rui Dang;Jie Liu;Jue-Yu Zhou-Jue-Yu-Z
背景越来越多的证据表明非编码RNA（lncRNA）参与了多种人类肿瘤的发生。然而，这些lncRNA在HPV驱动的宫颈癌（CC）中的作用尚未得到广泛研究。考虑到HR-HPV感染通过调节lncRNA、miRNAs和mRNAs的表达而促进宫颈癌的发生，我们的目的是系统地分析lncRNA和mRNA表达谱，以确定新的lncRNAs-mRNAs共表达网络，并探讨其在HPV驱动的CC中的潜在影响。在HPV-16和HPV-18宫颈癌发生过程中，与正常宫颈组织相比，采用Venn图和加权基因共表达网络分析（WGCNA），对与HPV-16和HPV-18 CC患者相关的hub DElncRNA/DEmRNA进行分析。对HPV-16和HPV-18 CC患者中这些关键DElncRNA/DEmRNAs进行LncRNA-mRNA相关性分析和功能富集途径分析，以探讨它们在HPV驱动CC中的相互作用机制。采用考克斯回归方法建立并验证lncRNA-mRNA共表达评分（CES）模型。比较两组患者的临床病理特征。进行体外功能实验以评估LINC 00511和PGK 1在CC细胞中的细胞增殖、迁移和侵袭中的作用。为了了解LINC 00511是否发挥致癌作用部分通过调节PGK 1的表达，救援assays were used.ResultsWe鉴定了81 lncRNAs和211 mRNA，通常差异表达的HPV-16和HPV-18 CC组织相比，正常组织。lncRNA-mRNA相关性分析和功能富集途径分析结果表明，LINC 00511-PGK 1共表达网络可能对HPV介导的肿瘤发生做出重要贡献，并与代谢相关机制密切相关。结合临床生存数据，基于LINC 00511和PGK 1的预后lncRNA-mRNA共表达评分（CES）模型可以准确预测患者的总生存期（OS）。高CES患者的预后比低CES患者差，在高CES患者中，可应用药物的富集途径和潜在靶点被探索，体外实验证实了LINC 00511和PGK 1在CC进展中的致癌作用，并揭示LINC 00511在CC细胞中的致癌作用部分通过调节PGK 1的表达。这些数据鉴定了共表达模块，其为理解HPV介导的肿瘤发生的发病机理提供了有价值的信息，这突出了LINC 00511-PGK 1共表达网络在宫颈癌发生中的关键功能。此外，我们的CES模型具有可靠的预测能力，可以将CC患者分为低风险和高风险的生存不良组。本研究提供了一种筛选预后生物标志物的生物信息学方法，从而导致lncRNA-mRNA共表达网络的识别和构建，用于患者的生存预测和其他癌症的潜在药物应用。
BackgroundMounting evidence suggests that noncoding RNAs (lncRNAs) were involved in various human cancers. However, the role of these lncRNAs in HPV-driven cervical cancer (CC) has not been extensively studied. Considering that HR-HPV infections contribute to cervical carcinogenesis by regulating the expression of lncRNAs, miRNAs and mRNAs, we aim to systematically analyze lncRNAs and mRNAs expression profile to identify novel lncRNAs-mRNAs co-expression networks and explore their potential impact on tumorigenesis in HPV-driven CC.MethodsLncRNA/mRNA microarray technology was utilized to identify the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) in HPV-16 and HPV-18 cervical carcinogenesis compared to normal cervical tissues. Venn diagram and weighted gene co-expression network analysis (WGCNA) were used to identify the hub DElncRNAs/DEmRNAs that were both significantly correlated with HPV-16 and HPV-18 CC patients. LncRNA-mRNA correlation analysis and functional enrichment pathway analysis were performed on these key DElncRNAs/DEmRNAs in HPV-16 and HPV-18 CC patients to explore their mutual mechanism in HPV-driven CC. A lncRNA-mRNA co-expression score (CES) model was established and validated by using the Cox regression method. Afterward, the clinicopathological characteristics were analyzed between CES-high and CES-low groups. Invitro,functional experiments were performed to evaluate the role of LINC00511 and PGK1 in cell proliferation, migration and invasion in CC cells. To understand whether LINC00511 play as an oncogenic role partially via modulating the expression of PGK1, rescue assays were used.ResultsWe identified 81 lncRNAs and 211 mRNAs that were commonly differentially expressed in HPV-16 and HPV-18 CC tissues compared to normal tissues. The results of lncRNA-mRNA correlation analysis and functional enrichment pathway analysis showed that the LINC00511-PGK1 co-expression network may make an important contribution to HPV-mediated tumorigenesis and be closely associated with metabolism-related mechanisms. Combined with clinical survival data, the prognostic lncRNA-mRNA co-expression score (CES) model based on LINC00511 and PGK1 could precisely predict patients’ overall survival (OS). CES-high patients had a worse prognosis than CES-low patients and the enriched pathways and potential targets of applicable drugs were explored in CES-high patients.In vitroexperiments confirmed the oncogenic functions of LINC00511 and PGK1 in the progression of CC, and revealed that LINC00511 functions in an oncogenic role in CC cells partially via modulating the expression of PGK1.ConclusionsTogether, these data identify co-expression modules that provide valuable information to understand the pathogenesis of HPV-mediated tumorigenesis, which highlights the pivotal function of the LINC00511-PGK1 co-expression network in cervical carcinogenesis. Furthermore, our CES model has a reliable predicting ability that could stratify CC patients into low- and high-risk groups of poor survival. This study provides a bioinformatics method to screen prognostic biomarkers which leads to lncRNA-mRNA co-expression network identification and construction for patients’ survival prediction and potential drug applications in other cancers.