Department of General Surgery, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
Funct Integr Genomics. 2023 Aug 4;23(3):263. doi: 10.1007/s10142-023-01158-1.
Ubiquitination-related genes (URGs) exerted a crucial part in a variety of human disease disorders; however, their association with pancreatic adenocarcinoma (PAAD) had yet to be clearly described. We aimed to comprehensively characterize the contributions of URGs in PAAD through in silico analysis and experimental validation, and then identified a robust mRNA-lncRNA-based molecular prognostic panel for patients with PAAD using bulk RNA-sequencing and single-cell RNA-sequencing data. Initially, we collected the multi-omics data from TCGA platform to depict a comprehensive landscape of URGs in pan-cancer. Furthermore, we were accurate to PAAD for in-depth analysis. Significant differences of the activation of ubiquitination pathways and the expression of URGs were detected between normal and malignant cells. Unsupervised hierarchical clustering determined two PAAD subtypes with distinct clinical outcomes, ubiquitination pathway activities, immune microenvironment, and functional annotation characteristics. The expression profiles of ubiquitination-associated mRNAs and lncRNAs in the training and validation datasets were utilized to develop and verify a novel ubiquitination-related mRNA-lncRNA prognostic panel, which had a satisfied prediction efficiency. Our ubiquitination-associated model could function as an effective prognostic index and outperformed four other recognized panels in evaluating PAAD patients' survival status. Tumor immune microenvironment, mutation burden, and chemotherapy response were intensively explored to demonstrate the underlying mechanism of prognostic difference according to our panel. Our findings also revealed that FTI-277, a farnesyltransferase inhibitor, had a better curative effect in high-risk patients, while MK-2206, an Akt allosteric inhibitor, had a superior therapeutic effect in low-risk patients. The real-time PCR results uncovered the RNA expression of AC005062.1 in all the three PAAD cell lines was elevated several thousandfold. In conclusion, our URGs-based classification panel could be triumphantly served as a prediction tool for survival evaluation in patients with PAAD, and the genes in this panel could be developed as a potential target in PAAD therapy.
泛素化相关基因（URGs）在多种人类疾病中发挥着至关重要的作用；然而，它们与胰腺导管腺癌（PAAD）的关联尚未得到明确描述。我们旨在通过计算机分析和实验验证，全面描述 URGs 在 PAAD 中的作用，并利用批量 RNA 测序和单细胞 RNA 测序数据，为 PAAD 患者确定一个稳健的基于 mRNA-lncRNA 的分子预后模型。首先，我们从 TCGA 平台收集了多组学数据，以描绘泛癌中 URGs 的综合图谱。此外，我们还对 PAAD 进行了深入分析。在正常细胞和恶性细胞之间检测到泛素化途径的激活和 URGs 的表达存在显著差异。无监督层次聚类确定了两种具有不同临床结局、泛素化途径活性、免疫微环境和功能注释特征的 PAAD 亚型。在训练和验证数据集的泛素化相关 mRNAs 和 lncRNAs 的表达谱被用于开发和验证一个新的泛素化相关 mRNA-lncRNA 预后模型，该模型具有令人满意的预测效率。我们的泛素化相关模型可以作为一种有效的预后指标，在评估 PAAD 患者的生存状态方面优于其他四个公认的模型。我们还深入探讨了肿瘤免疫微环境、突变负担和化疗反应，以根据我们的模型阐明预后差异的潜在机制。我们的研究结果还表明，法尼基转移酶抑制剂 FTI-277 在高危患者中具有更好的治疗效果，而 Akt 变构抑制剂 MK-2206 在低危患者中具有更好的治疗效果。实时 PCR 结果揭示了 AC005062.1 在所有三种 PAAD 细胞系中的 RNA 表达都升高了数千倍。总之，我们基于 URGs 的分类模型可以成功地作为 PAAD 患者生存评估的预测工具，该模型中的基因可以作为 PAAD 治疗的潜在靶点。
