Biomedicine

CLC number: R734

ATP-Related Proteins Were Associated with Hürthle Cell Carcinomas Identified by Bioinformatic Analysis and Immunohistochemistry

ATP相关蛋白与Hürthle细胞癌的生物信息学和免疫组化研究

¹ Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430072, Hubei, China (武汉大学人民医院　乳腺甲状腺外科，湖北　武汉　430072)
² Information Center, Renmin Hospital of Wuhan University, Wuhan 430072, Hubei, China (武汉大学人民医院　信息中心，湖北　武汉　430072)
³ Department of Thyroid Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang, China (浙江大学医学院第一附属医院　甲状腺外科，浙江　杭州　310000)

^† Corresponding author. E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. ; This email address is being protected from spambots. You need JavaScript enabled to view it.

Received: 16 September 2024

Abstract

The past few decades witnessed a significant increase in the incidence of thyroid cancer worldwide. Hürthle cell carcinoma (HCC), which was also known as oncocytic carcinoma of the thyroid, was reclassified as a distinct histological type of thyroid cancer by the WHO in 2022. Although HCC has a relative poorer prognosis and is generally insensitive to radioiodine treatment, the mechanisms behind HCC are poorly understood currently. In this paper, ioinformatics methods were employed to identify differentially expressed proteins (DEPs) and to analyze their functions in disease. R project was used to identify DEPs in HCC and Hürthle cell adenoma (HCA) with data from the iProx database. DEPs were annotated using the DAVID tool. Protein-protein interaction networks were constructed and visualized using the STRING database and the Cytoscape software. NetworkAnalyst was used to explore the relationships of DEPs, transcription factors, diseases, and drugs. The predicting ability of DEPs were evaluated with receiver operating characteristic (ROC) curves. Three DEPs with best performance were validated using immunohistochemistry. Experimental results show that a total of 793 and 295 DEPs were identified in HCC-normal and HCA-normal comparisons, respectively. The common DEPs of the two comparisons included ATP5F1A, ATP5F1B, UQCRFS1, ATP5F1D, ATP5F1C, COX5A, ATP5PD, ATP5PO, SUCLG1, and ACO2. The ROC analysis showed that ATP5F1B, ATP5F1C, and ATP5PD demonstrated the highest diagnostic accuracy, as indicated by their area under the curve (AUC) values, highlighting their superior performance. Immunohistochemistry confirmed the upregulation of the three proteins in HCC. Differential expression analysis revealed DEPs as potential biomarkers for HCC and HCA. Notably, the most dysregulated proteins are generally involved in the assembly of complex V, indicating a potential association between oxidative phosphorylation and the carcinogenesis of HCC.

摘要

近几十年来，全球甲状腺癌发病率呈显著上升趋势。Hürthle 细胞癌(Hürthle cell carcinoma)又称甲状腺嗜酸细胞癌，2022 年 WHO 已将其划分为独立的甲状腺癌组织学亚型。该肿瘤预后相对较差，且对放射性碘治疗普遍不敏感，其发病机制目前仍不明确。本研究基于蛋白质组学公共数据库 iProx，利用 R 软件筛选 Hürthle 细胞癌(HCC)与 Hürthle 细胞腺瘤(HCA)相对于正常组织的差异表达蛋白(DEPs)，并通过 DAVID 进行功能富集注释；利用 STRING 及 Cytoscape 构建并可视化蛋白质相互作用网络；通过 NetworkAnalyst 分析差异蛋白与转录因子、疾病及药物的相互关系；采用 ROC 曲线评估核心基因的诊断效能，并通过免疫组化对关键分子进行验证。结果显示，HCC 组与正常组比较获得 793 个差异蛋白，HCA 组与正常组比较获得 295 个差异蛋白；取交集得到共同差异蛋白，并进一步筛选出 10 个核心基因，包括 ATP5F1A、 ATP5F1B、 UQCRFS1、 ATP5F1D、 ATP5F1C、 COX5A、 ATP5PD、 ATP5PO、 SUCLG1、 ACO2。ROC 曲线表明 ATP5F1B、 ATP5F1C、 ATP5PD 具有极高的诊断价值；免疫组化结果证实三者在 Hürthle 细胞癌中表达显著上调。综上，本研究发现多数异常表达蛋白参与线粒体复合物 V 组装，提示氧化磷酸化异常可能与 Hürthle 细胞癌的发生发展密切相关。