Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Front Endocrinol (Lausanne). 2023 Jul 18;14:1149997. doi: 10.3389/fendo.2023.1149997. eCollection 2023.
Pituitary neuroendocrine tumors (PitNETs), which originate from the pituitary gland, account for 10%-15% of all intracranial neoplasms. Recent studies have indicated that enhancer RNAs (eRNAs) exert regulatory effects on tumor growth. However, the mechanisms underlying the eRNA-mediated tumorigenesis of PitNETs have not been elucidated.
Normal pituitary and PitNETs tissues were used to identify the differentially expressed eRNAs (DEEs). Immune gene sets and hallmarks of cancer gene sets were quantified based on single sample gene set enrichment analysis (ssGSEA) algorithm using GSVA. The perspective of immune cells among all samples was calculated by the CIBERSORT algorithm. Moreover, the regulatory network composed of key DEEs, target genes of eRNAs, hallmarks of cancer gene sets, differentially expressed TF, immune cells and immune gene sets were constructed by Pearson correlation analysis. Small molecular anti-PitNETs drugs were explored by CMap analysis and the accuracy of the study was verified by and experiments, ATAC-seq and ChIP-seq.
In this study, data of 134 PitNETs and 107 non-tumorous pituitary samples were retrieved from a public database to identify differentially expressed genes. In total, 1128 differentially expressed eRNAs (DEEs) (494 upregulated eRNAs and 634 downregulated eRNAs) were identified. Next, the correlation of DEEs with cancer-related and immune-related gene signatures was examined to establish a co-expression regulatory network comprising 18 DEEs, 50 potential target genes of DEEs, 5 cancer hallmark gene sets, 2 differentially expressed transcription factors, 4 immune cell types, and 4 immune gene sets. Based on this network, the following four therapeutics for PitNETs were identified using Connectivity Map analysis: ciclopirox, bepridil, clomipramine, and alexidine. The growth-inhibitory effects of these therapeutics were validated using experiments. Ciclopirox exerted potential growth-inhibitory effects on PitNETs. Among the DEEs, , and were determined to be potential diagnostic and therapeutic biomarkers for PitNETs.
This study illustrated the significant influence of eRNAs on the occurrence and development of PitNETs. By constructing the co-expression regulation network, , and were identified as relatively significant DEEs which were considered as the novel biomarkers of diagnosis and treatment of PitNETs. This study demonstrated the roles of eRNAs in the occurrence and development of PitNETs and revealed that ciclopirox was a potential therapeutic for pituitary adenomas.
垂体神经内分泌肿瘤（PitNETs）起源于垂体，占所有颅内肿瘤的 10%-15%。最近的研究表明，增强子 RNA（eRNAs）对肿瘤生长具有调节作用。然而，PitNETs 中 eRNA 介导的肿瘤发生机制尚不清楚。
使用正常垂体和 PitNETs 组织鉴定差异表达的 eRNAs（DEEs）。使用 GSVA 算法基于单样本基因集富集分析（ssGSEA）量化免疫基因集和癌症基因集特征。通过 CIBERSORT 算法计算所有样本中免疫细胞的视角。此外，通过 Pearson 相关分析构建由关键 DEEs、eRNAs 的靶基因、癌症基因集特征、差异表达的 TF、免疫细胞和免疫基因集组成的调控网络。通过 CMap 分析探索小分子抗 PitNETs 药物，并通过 和 实验、ATAC-seq 和 ChIP-seq 验证研究的准确性。
本研究从公共数据库中检索了 134 例 PitNETs 和 107 例非肿瘤性垂体样本的数据，以鉴定差异表达基因。总共鉴定出 1128 个差异表达的 eRNAs（DEEs）（494 个上调的 eRNAs 和 634 个下调的 eRNAs）。接下来，检查 DEEs 与癌症相关和免疫相关基因特征的相关性，以建立包含 18 个 DEEs、50 个 DEEs 潜在靶基因、5 个癌症特征基因集、2 个差异表达转录因子、4 种免疫细胞类型和 4 个免疫基因集的共表达调控网络。基于该网络，通过连接组分析识别了用于治疗 PitNETs 的四种药物：环吡酮、贝普里啶、氯米帕明和阿利西丁。使用 实验验证了这些治疗药物的生长抑制作用。环吡酮对 PitNETs 具有潜在的生长抑制作用。在 DEEs 中， ， 和 被确定为 PitNETs 的潜在诊断和治疗生物标志物。
本研究说明了 eRNAs 对 PitNETs 的发生和发展有重要影响。通过构建共表达调控网络，鉴定出 ， 和 为相对显著的 DEEs，可作为 PitNETs 诊断和治疗的新型生物标志物。本研究证明了 eRNAs 在 PitNETs 的发生和发展中的作用，并揭示了环吡酮可能是一种治疗垂体腺瘤的潜在药物。
