Identification and validation of long noncoding RNA AC083900.1 and RP11-283C24.1 for prediction of progression of osteosarcoma

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2023-07-01 DOI:10.1016/j.mrfmmm.2023.111828

Liangkun Huang , Wenyi Jin , Yucheng Bao , Xiaoshuang Zeng , Yubiao Zhang , Jianlin Zhou , Hao Peng

{"title":"Identification and validation of long noncoding RNA AC083900.1 and RP11-283C24.1 for prediction of progression of osteosarcoma","authors":"Liangkun Huang , Wenyi Jin , Yucheng Bao , Xiaoshuang Zeng , Yubiao Zhang , Jianlin Zhou , Hao Peng","doi":"10.1016/j.mrfmmm.2023.111828","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>The role of cuproptosis, an emerging cell death pathway that makes a remarkable contribution to tumor progression, remains elusive in osteosarcoma<span> (OS), in addition to its regulator, including long-no-coding RNAs (lncRNAs) that are also a critical factor for fueling OS.</span></p></div><div><h3>Methods</h3><p>Transcriptome and clinical data from 70 normal human bone tissue samples and 84 frozen clinical osteosarcoma samples were included in this study. Cuproptosis-associated lncRNAs (CRlncs) were identified through differential expression and co-expression analyses. Univariate Cox regression was performed to screen for prognostic lncRNAs, then we used least absolute shrinkage and selection operator regression to distinguish prognosis-related CRlncs (AC083900.1 and RP11-283C24.1) for modeling the CRlncs prognostic signature (CLPS) by multivariate Cox regression using the stepwise method. CLPS performance was tested by independent prognostic analyses, survival curve and receiver operating characteristic (ROC) curve. In addition, the molecular and immune mechanisms that underlie the unfavorable prognosis of CLPS-identified high-risk group were elucidated.</p></div><div><h3>Result</h3><p><span><span>AC083900.1 and RP11–283C24.1 have been identified as the most important CRlncs for OS progression (hazard ratio: 3.498 and 2.724, respectively), and the derived CLPS demonstrated outstanding performance for the prediction of OS prognosis (AUC of 0.799 and 0.778 in the training and test sets, both adj-p < 0.05 in survival curve). As was anticipated, CLPS also outperformed a recent clinical prognostic approach that only achieved an AUC of 0.682 [metastasis]. It is notable that AC083900.1 progressed OS metastasis, evidenced by its high expression in metastatic OS, its high correlation to metastasis-related genes, and its high AUC of 0.683 for the prediction of metastasis. Mechanistically, AC083900.1 and RP11–283C24.1 dysregulated many critical biological processes regarding </span>humoral immune response, immunoglobulin complex, etc.; while reducing the </span>infiltration<span> of many cytotoxic immune cells<span> (B-cells, TIL, neutrophils, etc.). It is encouraging that BMS-509744 and KIN001–135 demonstrated high therapeutic implications for CLPS-identified high-risk OS, and the low-risk counterpart was sensitive to SB-216763. Quantitative RT-PCR analysis showed that both AC083900.1 and RP11-283C24.1 were significantly upregulated in different osteosarcoma cell lines.</span></span></p></div><div><h3>Conclusion</h3><p>This study elucidated the roles and mechanisms of AC083900.1 and RP11-283C24.1 in the development of OS, fostering a reliable prognostic approach and treatment for OS patients.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"827 ","pages":"Article 111828"},"PeriodicalIF":1.5000,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"4","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0027510723000155","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}

引用次数: 4

Abstract

Background

The role of cuproptosis, an emerging cell death pathway that makes a remarkable contribution to tumor progression, remains elusive in osteosarcoma (OS), in addition to its regulator, including long-no-coding RNAs (lncRNAs) that are also a critical factor for fueling OS.

Methods

Transcriptome and clinical data from 70 normal human bone tissue samples and 84 frozen clinical osteosarcoma samples were included in this study. Cuproptosis-associated lncRNAs (CRlncs) were identified through differential expression and co-expression analyses. Univariate Cox regression was performed to screen for prognostic lncRNAs, then we used least absolute shrinkage and selection operator regression to distinguish prognosis-related CRlncs (AC083900.1 and RP11-283C24.1) for modeling the CRlncs prognostic signature (CLPS) by multivariate Cox regression using the stepwise method. CLPS performance was tested by independent prognostic analyses, survival curve and receiver operating characteristic (ROC) curve. In addition, the molecular and immune mechanisms that underlie the unfavorable prognosis of CLPS-identified high-risk group were elucidated.

Result

AC083900.1 and RP11–283C24.1 have been identified as the most important CRlncs for OS progression (hazard ratio: 3.498 and 2.724, respectively), and the derived CLPS demonstrated outstanding performance for the prediction of OS prognosis (AUC of 0.799 and 0.778 in the training and test sets, both adj-p < 0.05 in survival curve). As was anticipated, CLPS also outperformed a recent clinical prognostic approach that only achieved an AUC of 0.682 [metastasis]. It is notable that AC083900.1 progressed OS metastasis, evidenced by its high expression in metastatic OS, its high correlation to metastasis-related genes, and its high AUC of 0.683 for the prediction of metastasis. Mechanistically, AC083900.1 and RP11–283C24.1 dysregulated many critical biological processes regarding humoral immune response, immunoglobulin complex, etc.; while reducing the infiltration of many cytotoxic immune cells (B-cells, TIL, neutrophils, etc.). It is encouraging that BMS-509744 and KIN001–135 demonstrated high therapeutic implications for CLPS-identified high-risk OS, and the low-risk counterpart was sensitive to SB-216763. Quantitative RT-PCR analysis showed that both AC083900.1 and RP11-283C24.1 were significantly upregulated in different osteosarcoma cell lines.

Conclusion

This study elucidated the roles and mechanisms of AC083900.1 and RP11-283C24.1 in the development of OS, fostering a reliable prognostic approach and treatment for OS patients.

查看原文本刊更多论文

长非编码RNA AC083900.1和RP11-283C24.1预测骨肉瘤进展的鉴定和验证

背景铜中毒是一种新出现的细胞死亡途径，对肿瘤进展有显著贡献，除其调节因子外，它在骨肉瘤（OS）中的作用仍然难以捉摸，包括长链非编码RNA（lncRNA），这也是促进OS的关键因素。方法本研究包括70份正常人骨组织样本和84份冷冻临床骨肉瘤样本的转录组和临床数据。通过差异表达和共表达分析鉴定了与脱发相关的lncRNA（CRlncs）。进行单变量Cox回归以筛选预后lncRNA，然后我们使用最小绝对收缩和选择算子回归来区分预后相关的CRlncs（AC083900.1和RP11-283C24.1），以通过使用逐步方法的多变量Cox回归来建模CRlncs预后特征（CLPS）。CLPS性能通过独立预后分析、生存曲线和受试者操作特征（ROC）曲线进行测试。此外，阐明了CLPS高危人群不良预后的分子和免疫机制。结果AC083900.1和RP11–283C24.1已被确定为OS进展中最重要的CRlncs（风险比分别为3.498和2.724），并且衍生的CLPS在预测OS预后方面表现出色（训练和测试集的AUC分别为0.799和0.778，生存曲线中均为adj-p<；0.05）。正如预期的那样，CLPS也优于最近的临床预后方法，该方法仅实现了0.682的AUC[转移]。值得注意的是，AC083900.1进展为OS转移，其在转移性OS中的高表达、与转移相关基因的高相关性以及预测转移的0.683的高AUC证明了这一点。从机制上讲，AC083900.1和RP11–283C24.1失调了许多关键的生物学过程，如体液免疫反应、免疫球蛋白复合物等。；同时减少许多细胞毒性免疫细胞（B细胞、TIL、中性粒细胞等）的浸润。令人鼓舞的是，BMS-509744和KIN01-135对CLPS确定的高风险OS表现出高治疗意义，而低风险对应物对SB-216763敏感。定量RT-PCR分析显示，AC083900.1和RP11-283C24.1在不同骨肉瘤细胞系中均显著上调。结论本研究阐明了AC083900.1和RP11-283C24.1在OS发生中的作用和机制，为OS患者提供了可靠的预后方法和治疗方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.