未经证实:溴结构域和细胞外末端(BET)家族(包括BRD2,BRD3和BRD4)被认为是癌细胞生长的主要驱动力和癌症治疗的新靶标。目前,在临床前和临床试验中,超过30种靶向抑制剂对各种肿瘤显示出显著的抑制作用。然而,表达水平,基因调控网络,预后价值,BRD2,BRD3和BRD4在肾上腺皮质癌(ACC)中的目标预测尚未完全阐明。因此,本研究旨在系统分析表达,基因调控网络,预后价值,ACC患者BRD2、BRD3和BRD4的目标预测,并阐明了BET家族表达与ACC之间的关联。我们还提供了有关BRD2,BRD3和BRD4的有用信息以及ACC临床治疗的潜在新靶标。
UNASSIGNED:我们系统地分析了表达式,预后,基因调控网络,以及使用多个在线数据库的ACC中BRD2、BRD3和BRD4的监管目标,包括cBioPortal,信任,遗传狂躁症,GEPIA,Metascape,UALCAN,LinkedOmics,和定时器。
UNASSIGNED:在不同癌症分期的ACC患者中,BRD3和BRD4的表达水平显著上调。此外,BRD4的表达与ACC的病理分期显著相关。具有低BRD2、BRD3和BRD4表达的ACC患者比具有高BRD2、BRD3和BRD4表达的患者具有更长的生存期。BRD2、BRD3和BRD4的表达改变5%,5%,75例ACC患者中占12%,分别。这些ACC患者中50个最常改变的BRD2、BRD3和BRD4邻近基因的基因改变频率≥25.00%,≥25.00%,≥44.44%,分别。BRD2,BRD3和BRD4及其邻近基因主要通过共表达形成复杂的相互作用网络,物理相互作用,和共享的蛋白质结构域。与BRD2,BRD3和BRD4及其邻近基因相关的分子功能主要包括蛋白质-大分子衔接子活性,细胞粘附分子结合,和芳香化酶活性。趋化因子信号通路,硫胺素代谢,根据KEGG途径分析,嗅觉转导被发现是富集的。SP1、NPM1、STAT3和TP53是BRD2、BRD4及其邻近基因的关键转录因子。MiR-142-3P,miR-484和miR-519C是BRD2、BRD3、BRD4及其邻近基因的主要miRNA靶标。我们分析了79例ACC患者的mRNA测序数据,发现ZSCAN12,DHX16,PRPF4B,EHMT1,CDK5RAP2,POMT1,WIZ,ZNF543和AKAP8是表达与BRD2、BRD3和BRD4表达呈正相关的前9个基因。BRD2、BRD3和BRD4的表达水平与B细胞和树突状细胞浸润水平呈正相关。BRD4靶向药物PFI-1和(BRD2、BRD3和BRD4)靶向药物I-BET-151可能对SW13细胞系具有良好的抑制作用。
UNASSIGNED:这项研究的发现为BRD2,BRD3和BRD4在ACC发生和发展中的作用提供了部分依据。此外,这项研究也为ACC提供了新的潜在治疗靶点,为今后的基础和临床研究提供参考。
Bromodomain and extracellular terminal (BET) family (including BRD2, BRD3, and BRD4) is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Currently, more than 30 targeted inhibitors have shown significant inhibitory effects against various tumors in preclinical and clinical trials. However, the expression levels, gene regulatory networks, prognostic value, and target prediction of BRD2, BRD3, and BRD4 in adrenocortical carcinoma (ACC) have not been fully elucidated. Therefore, this study aimed to systematically analyze the expression, gene regulatory network, prognostic value, and target prediction of BRD2, BRD3, and BRD4 in patients with ACC, and elucidated the association between BET family expression and ACC. We also provided useful information on BRD2, BRD3, and BRD4 and potential new targets for the clinical treatment of ACC.
We systematically analyzed the expression, prognosis, gene regulatory network, and regulatory targets of BRD2, BRD3, and BRD4 in ACC using multiple online databases, including cBioPortal, TRRUST, GeneMANIA, GEPIA, Metascape, UALCAN, LinkedOmics, and TIMER.
The expression levels of BRD3 and BRD4 were significantly upregulated in ACC patients at different cancer stages. Moreover, the expression of BRD4 was significantly correlated with the pathological stage of ACC. ACC patients with low BRD2, BRD3, and BRD4 expressions had longer survival than patients with high BRD2, BRD3, and BRD4 expressions. The expression of BRD2, BRD3, and BRD4 was altered by 5%, 5%, and 12% in 75 ACC patients, respectively. The frequency of gene alterations in the 50 most frequently altered BRD2, BRD3, and BRD4 neighboring genes in these ACC patients were ≥25.00%, ≥25.00%, and ≥44.44%, respectively. BRD2, BRD3, and BRD4 and their neighboring genes form a complex network of interactions mainly through co-expression, physical interactions, and shared protein domains. Molecular functions related to BRD2, BRD3, and BRD4 and their neighboring genes mainly include protein-macromolecule adaptor activity, cell adhesion molecule binding, and aromatase activity. Chemokine signaling pathway, thiamine metabolism, and olfactory transduction were found to be enriched as per the KEGG pathway analysis. SP1, NPM1, STAT3, and TP53 are key transcription factors for BRD2, BRD4, and their neighboring genes. MiR-142-3P, miR-484, and miR-519C were the main miRNA targets of BRD2, BRD3, BRD4, and their neighboring genes. We analyzed the mRNA sequencing data from 79 patients with ACC and found that ZSCAN12, DHX16, PRPF4B, EHMT1, CDK5RAP2, POMT1, WIZ, ZNF543, and AKAP8 were the top nine genes whose expression were positively associated with BRD2, BRD3, and BRD4 expression. The expression level of BRD2, BRD3, and BRD4 positively correlated with B cell and dendritic cell infiltration levels. BRD4-targeted drug PFI-1 and (BRD2, BRD3, and BRD4)-targeted drug I-BET-151 may have good inhibitory effects on the SW13 cell line.
The findings of this study provide a partial basis for the role of BRD2, BRD3, and BRD4 in the occurrence and development of ACC. In addition, this study also provides new potential therapeutic targets for ACC, which can serve as a reference for future basic and clinical research.