Transcriptome-based identification of key actin-binding proteins associated with high metastatic potential in breast cancer

IF 3.9 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Frontiers in Molecular Biosciences Pub Date : 2024-08-30 DOI:10.3389/fmolb.2024.1440276

Christian Müller, Leticia Oliveira-Ferrer, Volkmar Müller, Barbara Schmalfeldt, Sabine Windhorst

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Abstract

IntroductionActin-binding proteins (ABPs) are essential for the regulation of morphological plasticity required for tumor cells to metastasize. The aim of this study was to perform an unbiased bioinformatic approach to identify the key ABPs significantly associated with the metastatic potential of breast cancer cells.MethodsMicroarray data from 181 primary breast cancer samples from our hospital were used, and all genes belonging to the Gene Ontology term actin cytoskeleton organization were obtained from QuickGO. Association with metastasis-free survival probability was tested using Cox proportional hazards regression, and pairwise co-expression was tested by Pearson correlations. Differential expression between different subgroups was analyzed using Wilcoxon tests for dichotomous traits and Kruskal–Wallis tests for categorical traits. Validation was performed using four publicly available breast cancer datasets.ResultsARHGAP25 was significantly associated with a low metastatic potential, and CFL1, TMSB15A, and ACTL8 were significantly associated with a high metastatic potential. A significantly higher expression of CFL1, TMSB15A, and ACTL8 mRNA was found in the more aggressive Her2-positive and triple-negative subtypes as well as in ER-negative samples. Also, these genes were co-expressed in the same tumors. However, only mRNA levels of CFL1 were increased in pN1 compared to pN0 patients. External validation revealed that CFL1 and TMSB15A had significant associations with consistent hazard ratios in two breast cancer cohorts, and among these, CFL1 exhibited the highest hazard ratios.ConclusionCFL1 showed the strongest correlation with the metastatic potential of breast tumors. Thus, targeted inhibition of CFL1 might be a promising approach to treat malignant breast cancer cells.

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基于转录组鉴定与乳腺癌高转移潜能相关的关键肌动蛋白结合蛋白

引言肌动蛋白结合蛋白（ABPs）是调控肿瘤细胞转移所需的形态可塑性的关键。本研究旨在采用一种无偏见的生物信息学方法，鉴定与乳腺癌细胞转移潜能显著相关的关键 ABPs。方法使用本院 181 例原发性乳腺癌样本的微阵列数据，并从 QuickGO 中获取属于基因本体术语肌动蛋白细胞骨架组织的所有基因。用Cox比例危险度回归检验与无转移生存概率的关系，用Pearson相关性检验配对共表达。对二分性状采用 Wilcoxon 检验，对分类性状采用 Kruskal-Wallis 检验，分析不同亚组之间的表达差异。结果ARHGAP25与低转移潜能显著相关，CFL1、TMSB15A和ACTL8与高转移潜能显著相关。在侵袭性较强的 Her2 阳性和三阴性亚型以及 ER 阴性样本中，CFL1、TMSB15A 和 ACTL8 mRNA 的表达量明显较高。而且，这些基因在相同的肿瘤中共同表达。不过，与 pN0 患者相比，pN1 患者中只有 CFL1 的 mRNA 水平升高。外部验证显示，在两个乳腺癌队列中，CFL1 和 TMSB15A 与一致的危险比有显著关联，其中 CFL1 的危险比最高。因此，靶向抑制 CFL1 可能是治疗恶性乳腺癌细胞的一种有前途的方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Molecular Biosciences Biochemistry, Genetics and Molecular Biology-Biochemistry

CiteScore

7.20

自引率

4.00%

发文量

1361

审稿时长

14 weeks

期刊介绍： Much of contemporary investigation in the life sciences is devoted to the molecular-scale understanding of the relationships between genes and the environment — in particular, dynamic alterations in the levels, modifications, and interactions of cellular effectors, including proteins. Frontiers in Molecular Biosciences offers an international publication platform for basic as well as applied research; we encourage contributions spanning both established and emerging areas of biology. To this end, the journal draws from empirical disciplines such as structural biology, enzymology, biochemistry, and biophysics, capitalizing as well on the technological advancements that have enabled metabolomics and proteomics measurements in massively parallel throughput, and the development of robust and innovative computational biology strategies. We also recognize influences from medicine and technology, welcoming studies in molecular genetics, molecular diagnostics and therapeutics, and nanotechnology. Our ultimate objective is the comprehensive illustration of the molecular mechanisms regulating proteins, nucleic acids, carbohydrates, lipids, and small metabolites in organisms across all branches of life. In addition to interesting new findings, techniques, and applications, Frontiers in Molecular Biosciences will consider new testable hypotheses to inspire different perspectives and stimulate scientific dialogue. The integration of in silico, in vitro, and in vivo approaches will benefit endeavors across all domains of the life sciences.