A multi-omics analysis reveals CLSPN is associated with prognosis, immune microenvironment and drug resistance in cancers.

IF 3.7 3区生物学 Q1 BIOCHEMICAL RESEARCH METHODS Biological Procedures Online Pub Date : 2023-06-03 DOI:10.1186/s12575-023-00201-6

Yihong Chen, Haicheng Wen, Yin Li, Ying Han, Jun Tan, Cao Guo, Changjing Cai, Ping Liu, Yinghui Peng, Yihan Liu, Xinwen Wang, Shan Zeng, Ziyang Feng, Hong Shen

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Abstract

Background: Immunotherapy is effective only in limited patients. It is urgent to discover a novel biomarker to predict immune cells infiltration status and immunotherapy response of different cancers. CLSPN has been reported to play a pivotal role in various biological processes. However, a comprehensive analysis of CLSPN in cancers has not been conducted.

Methods: To show the whole picture of CLSPN in cancers, a pan-cancer analysis was conducted in 9125 tumor samples across 33 cancer types by integrating transcriptomic, epigenomic and pharmacogenomics data. Moreover, the role of CLSPN in cancer was validated by CCK-8, EDU, colony formation and flow cytometry in vitro and tumor cell derived xenograft model in vivo.

Results: CLSPN expression was generally upregulated in most cancer types and was significantly associated with prognosis in different tumor samples. Moreover, elevated CLSPN expression was closely correlated with immune cells infiltration, TMB (tumor mutational burden), MSI (microsatellite instability), MMR (mismatch repair), DNA methylation and stemness score across 33 cancer types. Enrichment analysis of functional genes revealed that CLSPN participated in the regulation of numerous signaling pathways involved in cell cycle and inflammatory response. The expression of CLSPN in LUAD patients were further analyzed at the single-cell level. Knockdown CLSPN significantly inhibited cancer cell proliferation and cell cycle related cyclin-dependent kinase (CDK) family and Cyclin family expression in LUAD (lung adenocarcinoma) both in vitro and in vivo experiments. Finally, we conducted structure-based virtual screening by modelling the structure of CHK1 kinase domain and Claspin phosphopeptide complex. The top five hit compounds were screened and validated by molecular docking and Connectivity Map (CMap) analysis.

Conclusion: Our multi-omics analysis offers a systematic understanding of the roles of CLSPN in pan-cancer and provides a potential target for future cancer treatment.

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一项多组学分析显示CLSPN与癌症的预后、免疫微环境和耐药性有关。

背景:免疫疗法仅在有限的患者中有效。迫切需要一种新的生物标志物来预测不同肿瘤的免疫细胞浸润状态和免疫治疗反应。据报道，CLSPN在多种生物过程中起着关键作用。然而，尚未对癌症中的CLSPN进行全面分析。方法:通过整合转录组学、表观基因组学和药物基因组学数据，对33种癌症类型的9125例肿瘤样本进行泛癌分析，以展现CLSPN在癌症中的全貌。此外，通过体外CCK-8、EDU、集落形成和流式细胞术以及体内肿瘤细胞源异种移植模型验证了CLSPN在癌症中的作用。结果:CLSPN在大多数肿瘤类型中普遍表达上调，且在不同肿瘤样本中与预后显著相关。此外，在33种癌症类型中，CLSPN表达升高与免疫细胞浸润、TMB(肿瘤突变负担)、MSI(微卫星不稳定性)、MMR(错配修复)、DNA甲基化和干细胞评分密切相关。功能基因富集分析显示，CLSPN参与调控细胞周期和炎症反应的多种信号通路。在单细胞水平进一步分析LUAD患者CLSPN的表达情况。在体外和体内实验中，敲低CLSPN可显著抑制LUAD(肺腺癌)中癌细胞增殖和细胞周期相关的细胞周期蛋白依赖性激酶(Cyclin -dependent kinase, CDK)家族和Cyclin家族的表达。最后，我们通过模拟CHK1激酶结构域和Claspin磷酸肽复合物的结构进行了基于结构的虚拟筛选。通过分子对接和连通性图(CMap)分析，筛选前5个命中的化合物并进行验证。结论:我们的多组学分析提供了对CLSPN在泛癌中的作用的系统理解，并为未来的癌症治疗提供了潜在的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biological Procedures Online 生物-生化研究方法

CiteScore

10.50

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： iological Procedures Online publishes articles that improve access to techniques and methods in the medical and biological sciences. We are also interested in short but important research discoveries, such as new animal disease models. Topics of interest include, but are not limited to: Reports of new research techniques and applications of existing techniques Technical analyses of research techniques and published reports Validity analyses of research methods and approaches to judging the validity of research reports Application of common research methods Reviews of existing techniques Novel/important product information Biological Procedures Online places emphasis on multidisciplinary approaches that integrate methodologies from medicine, biology, chemistry, imaging, engineering, bioinformatics, computer science, and systems analysis.