基于 WGCNA 构建 RBP 基因签名用于结直肠癌预后预测的开发和验证。

Development and validation of an RBP gene signature for prognosis prediction in colorectal cancer based on WGCNA.

机构信息

Department of Biomedical Engineering, Air Force Hospital of Eastern Theater Command, 210001, Nanjing, Jiangsu Province, China.

Division of Digestive Surgery, State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 710032, Xi'an, Shaanxi Province, China.

出版信息

Hereditas. 2023 Mar 10;160(1):10. doi: 10.1186/s41065-023-00274-z.

DOI:10.1186/s41065-023-00274-z

PMID:36895014

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9999506/

Abstract

BACKGROUND

RNA binding proteins (RBPs) have been implicated in oncogenesis and progression in various cancers. However, the potential value of RBPs as prognostic indicators and therapeutic targets in colorectal cancer (CRC) requires further investigation.

METHODS

Four thousand eighty two RBPs were collected from literature. The weighted gene co-expression network analysis (WGCNA) was performed to identify prognosis-related RBP gene modules based on the data attained from the TCGA cohorts. LASSO algorithm was conducted to establish a prognostic risk model, and the validity of the proposed model was confirmed by an independent GEO dataset. Functional enrichment analysis was performed to reveal the potential biological functions and pathways of the signature and to estimate tumor immune infiltration. Potential therapeutic compounds were inferred utilizing CMap database. Expressions of hub genes were further verified through the Human Protein Atlas (HPA) database and RT-qPCR.

RESULTS

One thousand seven hundred thirty four RBPs were differently expressed in CRC samples and 4 gene modules remarkably linked to the prognosis were identified, based on which a 12-gene signature was established for prognosis prediction. Multivariate Cox analysis suggested this signature was an independent predicting factor of overall survival (P < 0.001; HR:3.682; CI:2.377-5.705) and ROC curves indicated it has an effective predictive performance (1-year AUC: 0.653; 3-year AUC:0.673; 5-year AUC: 0.777). GSEA indicated that high risk score was correlated with several cancer-related pathways, including cytokine-cytokine receptor cross talk, ECM receptor cross talk, HEDGEHOG signaling cascade and JAK/STAT signaling cascade. ssGSEA analysis exhibited a significant correlation between immune status and the risk signature. Noscapine and clofazimine were screened as potential drugs for CRC patients with high-risk scores. TDRD5 and GPC1 were identified as hub genes and their expression were validated in 15 pairs of surgically resected CRC tissues.

CONCLUSION

Our research provides a depth insight of RBPs' role in CRC and the proposed signature are helpful to the personalized treatment and prognostic judgement.

摘要

背景

RNA 结合蛋白（RBPs）已被证实与多种癌症的发生和进展有关。然而，RBPs 作为结直肠癌（CRC）预后指标和治疗靶点的潜在价值仍需进一步研究。

方法

从文献中收集了 4082 个 RBPs。基于 TCGA 队列获得的数据，采用加权基因共表达网络分析（WGCNA）方法鉴定与预后相关的 RBP 基因模块。通过 LASSO 算法建立预后风险模型，并通过独立的 GEO 数据集验证该模型的有效性。通过功能富集分析揭示特征的潜在生物学功能和途径，并估计肿瘤免疫浸润。利用 CMap 数据库推断潜在的治疗化合物。通过人类蛋白质图谱（HPA）数据库和 RT-qPCR 进一步验证核心基因的表达。

结果

在 CRC 样本中，有 1734 个 RBPs 表达差异，根据这些差异，确定了 4 个与预后显著相关的基因模块，并建立了一个 12 基因的预后预测签名。多因素 Cox 分析表明，该签名是总生存期的独立预测因素（P<0.001；HR：3.682；CI：2.377-5.705），ROC 曲线表明其具有有效的预测性能（1 年 AUC：0.653；3 年 AUC：0.673；5 年 AUC：0.777）。GSEA 分析表明，高风险评分与多种癌症相关途径相关，包括细胞因子-细胞因子受体相互作用、ECM 受体相互作用、HEDGEHOG 信号级联和 JAK/STAT 信号级联。ssGSEA 分析表明，免疫状态与风险签名之间存在显著相关性。筛选出诺斯卡品和氯法齐明作为高危评分 CRC 患者的潜在药物。鉴定出 TDRD5 和 GPC1 为核心基因，并在 15 对手术切除的 CRC 组织中验证了它们的表达。