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鉴定长链非编码 RNA 叉头框蛋白 P4 反义 RNA 1 在早期胰腺导管腺癌患者中的潜在临床意义。

Identify potential clinical significance of long noncoding RNA forkhead box P4 antisense RNA 1 in patients with early stage pancreatic ductal adenocarcinoma.

机构信息

Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province, People's Republic of China.

Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China.

出版信息

Cancer Med. 2020 Mar;9(6):2062-2076. doi: 10.1002/cam4.2818. Epub 2020 Jan 28.

DOI:10.1002/cam4.2818
PMID:31991068
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7064149/
Abstract

Previous studies have shown that forkhead box P4 antisense RNA 1 (FOXP4-AS1) is dysregulated in tumor tissues and can serve as a prognostic indicator for multiple cancers. However, the clinical significance of FOXP4-AS1 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The goal of this study is to recognize the possible clinical significance of long noncoding RNA FOXP4-AS1 in patients with early stage PDAC. A total of 112 patients from The Cancer Genome Atlas (TCGA) PDAC cohort, receiving RNA sequencing, were involved in the study. Survival analysis, functional mechanism, and potential small molecule drugs of target therapy of FOXP4-AS1 were performed in this study. Survival analysis in TCGA PDAC cohort suggested that patients with high FOXP4-AS1 expression had significantly augmented possibility of death than in PDAC patients with lower FOXP4-AS1 expression (adjusted P = .008; adjusted HR = 2.143, 95% CI = 1.221-3.760). In this study, a genome-wide RNA sequencing dataset was used to identify 927 genes co-expressing with FOXP4-AS1 in PDAC tumor tissues. A total of 676 differentially expressed genes were identified between different FOXP4-AS1 expression groups. Functional enrichment analysis of these genes and gene set enrichment analysis for PDAC genome-wide RNA sequencing dataset was done. We have found that FOXP4-AS1 may function in PDAC by participating in biological processes and pathways including oxidative phosphorylation, tricarboxylic acid cycle, classical tumor-related pathways such as NF-kappaB as well as Janus kinase/signal transducers in addition to activators of transcription, cell proliferation, and adhesion. In addition, we also screened two potential targeted therapeutic small molecule drugs (dimenhydrinate and metanephrine) for FOXP4-AS1 in PDAC. In conclusion, our present study demonstrated that higher expression of FOXP4-AS1 in PDAC tumor tissues were related with an inferior medical outcome. Through multiple genome-wide approaches, we identified the potential molecular mechanisms of FOXP4-AS1 in PDAC and two targeted therapeutic drugs for it.

摘要

先前的研究表明，叉头框 P4 反义 RNA 1（FOXP4-AS1）在肿瘤组织中失调，可作为多种癌症的预后指标。然而，FOXP4-AS1 在胰腺导管腺癌（PDAC）中的临床意义尚不清楚。本研究旨在探讨长链非编码 RNA FOXP4-AS1 在早期 PDAC 患者中的可能临床意义。本研究共纳入 112 名来自癌症基因组图谱（TCGA）PDAC 队列、接受 RNA 测序的患者。对 FOXP4-AS1 的生存分析、功能机制和潜在的靶向治疗小分子药物进行了研究。TCGA PDAC 队列的生存分析表明，FOXP4-AS1 高表达的患者死亡可能性明显高于 FOXP4-AS1 低表达的 PDAC 患者（调整后 P=0.008；调整后 HR=2.143，95%CI=1.221-3.760）。本研究使用全基因组 RNA 测序数据集来鉴定 PDAC 肿瘤组织中与 FOXP4-AS1 共表达的 927 个基因。在不同 FOXP4-AS1 表达组之间共鉴定出 676 个差异表达基因。对这些基因进行功能富集分析，并对 PDAC 全基因组 RNA 测序数据集进行基因集富集分析。我们发现，FOXP4-AS1 可能通过参与氧化磷酸化、三羧酸循环、经典肿瘤相关途径（如 NF-kappaB）以及转录激活物、细胞增殖和黏附等途径，在 PDAC 中发挥作用。此外，我们还筛选了两种针对 PDAC 的 FOXP4-AS1 潜在靶向治疗小分子药物（茶苯海明和间甲肾上腺素）。总之，本研究表明，PDAC 肿瘤组织中 FOXP4-AS1 的高表达与较差的预后相关。通过多种全基因组方法，我们鉴定了 FOXP4-AS1 在 PDAC 中的潜在分子机制和两种针对它的靶向治疗药物。

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