Exploring DNA topoisomerase II alpha in adrenocortical carcinoma through multi-omics analysis: a potential biomarker and therapeutic target

Abstract

Adrenocortical carcinoma (ACC) is a rare but aggressive cancer. Recent studies identified DNA Topoisomerase II Alpha (TOP2A) as a potential biomarker for ACC, which can provide new avenues for targeted therapy and improve clinical outcomes. This study aims to elucidate the role of TOP2A in ACC by exploring its prognostic value and identifying inhibitors for ACC therapy. Utilizing RNA sequencing data, mutation data, and clinical information from The Cancer Genome Atlas (TCGA-ACC) and additional datasets from the Gene Expression Omnibus (GEO), differential expression and prognostic analyses are conducted to assess the significance of TOP2A in ACC. Immunohistochemistry and cell assays, including cell viability, colony formation, and transwell assays, are conducted to validate the oncogenic effects of TOP2A. The “IOBR” R package is used to examine the relationship between TOP2A expression and CD8+ T-cell infiltration. The CMap platform is used to identify potential TOP2A inhibitors. In vivo assays verify the therapeutic effect of TOP2A inhibitors on ACC. Our findings indicate that TOP2A is significantly overexpressed in ACC and is associated with poor prognosis. Immunohistochemistry and cell assays confirm the oncogenic role of TOP2A. Furthermore, distinct gene expression patterns related to different TOP2A expression levels are identified, influencing the response to immunotherapy. Potential inhibitors targeting TOP2A are discovered, and the therapeutic effects of resminostat and etoposide are confirmed via in vivo assays, suggesting new therapeutic strategies for ACC treatment. In conclusion, TOP2A serves as a crucial biomarker in ACC and is associated with adverse clinical outcomes and a diminished immune response. The identification of potential inhibitors against TOP2A opens new avenues for the development of targeted therapies for ACC patients.

1. Introduction

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an annual incidence rate of 0.5–2 cases per million in adults and 0.2–0.3 cases per million in children [1,2]. Despite its rarity, ACC has a poor prognosis, with a 5-year survival rate of only 35% [3], which decreases to less than 10% in advanced stages [4]. Post-surgical resection often leads to local recurrence and distant metastases in nearly two-thirds of patients [3,5]. Mitotane is currently the sole chemotherapeutic agent for ACC, characterized by its inconsistent efficacy and severe side effects when used as a monotherapy [6,7]. Other treatments, such as the combination of etoposide, doxorubicin, and cisplatin with mitotane (EDP-M) and immunotherapy, have shown uncertain efficacy and severe adverse effects [8]. Similarly, the application of immunotherapy, which has garnered significant attention in recent years, continues to lead to unstable therapeutic outcomes in ACC, leading to numerous challenges [9]. Therefore, new biological markers and therapeutic targets for ACC are urgently needed.

The development of new biomarkers and therapeutic targets for ACC is challenging because of the pronounced heterogeneity of tumors [10–14]. Advances in high-throughput sequencing technologies have enabled multiomics approaches that integrate genomics, transcriptomics, proteomics, and more to explore the molecular heterogeneity of cancers [10]. This approach aids in identifying potential biomarkers and therapeutic targets and enhances our understanding of the complex biology of ACC.

DNA topoisomerase II alpha (TOP2A) encodes an essential enzyme that regulates chromosome condensation and sister chromatid separation by altering DNA topology during replication and transcription [15]. TOP2A is also involved in cell cycle regulation and DNA repair [16]. Studies have shown that TOP2A is overexpressed in various tumors, including hepatocellular carcinoma, non-small cell lung cancer, and breast cancer, where it is associated with aggressive tumor behavior and poor prognosis. However, its role in ACC remains underexplored, prompting this comprehensive multi-omics investigation.