A prospective prognostic signature for pancreatic adenocarcinoma based on ubiquitination-related mRNA-lncRNA with experimental validation in vitro and vivo.
A prospective prognostic signature for pancreatic adenocarcinoma based on ubiquitination-related mRNA-lncRNA with experimental validation in vitro and vivo.
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DOI：
10.1007/s10142-023-01158-1
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发表时间：
2023-08-04
影响因子：
2.9
通讯作者：
Shang, Dong
中科院分区：
文献类型：
--
作者：
Wang, Zhizhou;Yuan, Qihang;Chen, Xu;Luo, Fei;Shi, Xueying;Guo, Fangyue;Ren, Jie;Li, Shuang;Shang, Dong
关键词：
泛素化相关基因（Ubiquitination-related genes，URGs）在多种人类疾病中发挥着重要作用，但其与胰腺癌（pancreatic adenocarcinoma，PAAD）的关系尚不清楚。我们的目的是通过计算机模拟分析和实验验证来全面表征URG在PAAD中的贡献，然后使用批量RNA测序和单细胞RNA测序数据来确定PAAD患者的稳健的基于mRNA-lncRNA的分子预后面板。最初，我们从TCGA平台收集多组学数据，以描绘泛癌症中URG的全面景观。此外，我们对PAAD进行了准确的深入分析。在正常和恶性细胞中，泛素化途径的激活和URGs的表达存在显著差异。无监督分层聚类确定了两种PAAD亚型，其具有不同的临床结果、泛素化途径活性、免疫微环境和功能注释特征。利用训练数据集和验证数据集中泛素化相关mRNA和lncRNA的表达谱，建立并验证了一种新的预测模型，该模型具有较好的预测效果。我们的泛素化相关模型可以作为一个有效的预后指标，并优于其他四个公认的面板在评估PAAD患者的生存状态。根据我们的小组，深入研究了肿瘤免疫微环境、突变负荷和化疗反应，以证明预后差异的潜在机制。我们的研究结果还显示，法尼基转移酶抑制剂FTI-277在高危患者中具有更好的疗效，而Akt变构抑制剂MK-2206在低危患者中具有更好的上级疗效。实时荧光定量PCR检测结果显示，AC005062.1在三种PAAD细胞系中的RNA表达量均升高数千倍。总之，我们的URG分类面板可以成功地作为一个预测工具，生存评估与PAAD患者，和这个面板中的基因可以开发为一个潜在的目标，在PAAD治疗。在线版本包含补充材料，可通过10.1007/s10142-023-01158-1获得。
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. The online version contains supplementary material available at 10.1007/s10142-023-01158-1.
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影响因子：
12.4
作者：
Liu H;Qian F
通讯作者：
Qian F
影响因子：
2.9
作者：
Huang, Hao;Wei, Yaqing;Yao, Hao;Chen, Ming;Sun, Jinjin
通讯作者：
Sun, Jinjin
影响因子：
2.9
作者：
Lu，Jianzhong;Tan，Jinhua;Yu，Xiaoqing
通讯作者：
Yu，Xiaoqing
影响因子：
2.9
作者：
Li，Ruibin;Zhang，Shiyao;Liu，Gang
通讯作者：
Liu，Gang
DOI：
10.1158/1078-0432.ccr-14-3214
发表时间：
2015-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cox AD;Der CJ;Philips MR
通讯作者：
Philips MR