CPNE1的综合分析可预测胃腺癌的预后和耐药性。

Comprehensive analysis of CPNE1 predicts prognosis and drug resistance in gastric adenocarcinoma.

作者信息

Li Guangyao, Ping Miaomiao, Guo Jizheng, Wang Jin

机构信息

Department of Gastrointestinal Surgery, The Second People's Hospital of Wuhu Wuhu 241000, Anhui, China.

School of Basic Medical Sciences, Anhui Medical University Hefei 230032, Anhui, China.

出版信息

Am J Transl Res. 2024 Jun 15;16(6):2233-2247. doi: 10.62347/NIYR2094. eCollection 2024.

DOI:10.62347/NIYR2094

PMID:39006290

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11236623/

Abstract

BACKGROUND

Recent studies have confirmed that Copines-1 (CPNE1) is associated with many malignancies. However, the role of CPNE1 in stomach adenocarcinoma (STAD) is currently unclear.

METHODS

TIMER2.0, TCGA, UALCAN databases were used to investigate the expression of CPNE1 in STAD and normal tissues. KM-plotter database was used to explore the relationship between CPNE1 expression and prognosis in STAD. Immunohistochemistry (IHC) was used to assess the protein levels of CPNE1 in both normal and cancer tissues, as well as to confirm the prognostic significance of CPNE1. In order to assess the viability of CPNE1 as a divider, the Recipient Operating Characteristics (ROC) curve was employed and the assessment based on the AUC score (below the curve). To investigate the potential function of CPNE1, correlation analysis and enrichment analysis were performed with the clusterProfiler package in R software. The CPNE1 binding protein network was constructed by STRING and GeneMANIA. The relationship between methylation and prognosis was explored by Methsurv database. The Genomics of Drug Sensitivity in Cancer (GDSC) was employed to predict drug responsiveness in STAD. Ultimately, CCK-8 assays and RT-qPCR were performed to confirm the correlation between CPNE1 expression and the IC of Axitinib in the AGS cell line.

RESULT

CPNE1 is highly expressed in various cancers, including STAD. High expression of CPNE1 indicated poor overall survival (OS) of STAD ( < 0.05). The ROC curve suggested that CPNE1 was a potential diagnostic biomarker (AUC = 0.925). The functions of CPNE1 were enriched in DNA-acting catalytic activity, sulfur transferase activity, Ran GTPase binding, DNA helicase activity, helicase activity and eukaryotic ribosome biosynthesis. Hyper-methylated CPNE1 predicts better prognosis in STAD ( < 0.05). Additionally, STAD patients with high-expression CPNE1 seemed to be more resistant to the chemotherapeutic agents, including A-770041, WH-4-023, AZD-2281, AG-014699, AP-24534, Axitinib, AZD6244, RDEA119, AZD8055, Temsirolimus, Pazopanib and Roscovitine. In vitro experiments demonstrated the involvement of CPNE1 in Axitinib chemoresistance.

CONCLUSION

CPNE1 could be a predictive biomarker and a potential target for biological therapy in STAD.

摘要

背景

近期研究证实，Copines-1（CPNE1）与多种恶性肿瘤相关。然而，CPNE1在胃腺癌（STAD）中的作用目前尚不清楚。

方法

利用TIMER2.0、TCGA、UALCAN数据库研究CPNE1在STAD和正常组织中的表达。使用KM-plotter数据库探讨CPNE1表达与STAD预后的关系。免疫组织化学（IHC）用于评估正常组织和癌组织中CPNE1的蛋白水平，并确认CPNE1的预后意义。为了评估CPNE1作为一种分界点的可行性，采用受试者工作特征（ROC）曲线并基于曲线下面积（AUC）评分进行评估。为了研究CPNE1的潜在功能，使用R软件中的clusterProfiler包进行相关性分析和富集分析。通过STRING和GeneMANIA构建CPNE1结合蛋白网络。利用Methsurv数据库探索甲基化与预后的关系。采用癌症药物敏感性基因组学（GDSC）预测STAD中的药物反应性。最终，进行CCK-8试验和RT-qPCR以确认CPNE1表达与AGS细胞系中阿西替尼IC之间的相关性。

结果

CPNE1在包括STAD在内的多种癌症中高表达。CPNE1高表达表明STAD的总生存期（OS）较差（<0.05）。ROC曲线表明CPNE1是一种潜在的诊断生物标志物（AUC = 0.925）。CPNE1的功能富集于DNA作用催化活性、硫转移酶活性、Ran GTP酶结合、DNA解旋酶活性、解旋酶活性和真核核糖体生物合成。CPNE1高甲基化预测STAD预后较好（<0.05）。此外，CPNE1高表达的STAD患者似乎对包括A-770041、WH-4-023、AZD-2281、AG-014699、AP-24534、阿西替尼、AZD6244、RDEA119、AZD8055、替西罗莫司、帕唑帕尼和罗可替尼在内的化疗药物更具抗性。体外实验证明CPNE1参与阿西替尼化疗耐药。