Gliomas constitute ~80% of malignant brain tumors in adults, with GBM as the most prevalent type (34). A previously published study suggested that a link exists between human cytomegalovirus (HCMV) infection and GBM, which contributes to tumor growth and metastasis (35). The conventional treatment strategy for GBM involves total tumor resection followed by chemotherapy and radiation therapy. Despite these interventions, GBM remains largely untreatable, with a median survival time for patients of 15 months (36), underscoring the importance of early biomarker detection for managing glioma.

A previous study by Yang et al (37) demonstrated that TOP2A is upregulated in GBM, and that this upregulation is associated with a negative prognosis. Go-ichi-san complex subunit 1 (GINS1), which is prominently expressed in GBM, facilitates tumor cell proliferation and migration; on the other hand, silencing GINS1 impedes these processes. Ubiquitin-specific protease 15 (USP15), an enzyme that deubiquitinates and interacts with TOP2A, enhances the malignant characteristics of GBM through decreasing the ubiquitination of TOP2A. This interaction was shown to circumvent the inhibitory effects of silencing GINS1 on tumor growth and dissemination. It has been postulated that GINS1 may drive GBM advancement via the USP15-mediated deubiquitination of TOP2A, although the detailed mechanism requires further investigation (37). In addition, the presence of β-catenin, a key element of the Wnt signaling pathway, in GBM cells is positively associated with TOP2A expression. Through the dysregulation of Wnt/β-catenin signaling, known to foster the invasion and metastasis of various types of cancer, it has been inferred that TOP2A may be dependent on the β-catenin signaling pathway to promote glioma progression (38). A previous study has highlighted the significant roles of microRNAs (miRNAs or miRs), typically considered to be tumor suppressors, in controlling tumor development, growth, migration, invasion and apoptosis (39). Interestingly, a marked difference in miR-144-3p levels was observed between HCMV-positive and HCMV-negative GBM samples. A negative association was identified between the expression levels of miR-144-3p and TOP2A. Laboratory experiments have also demonstrated that miR-144-3p promotes apoptosis and diminishes cell migration through the targeting of TOP2A, thereby inhibiting glioma cell proliferation (35). Taken together, the aforementioned studies have revealed that unraveling the complex regulatory network involving TOP2A in GBM may offer new perspectives, and provide ideas for therapeutic strategies to enhance the prognosis for patients with GBM.

BC remains the most common cancer among women globally, and is the primary cause of cancer-associated mortality in women under the age of 40 (40–43). Predictions for 2024 estimate that there will be over 310,000 new diagnoses of, and more than 40,000 deaths resulting from, this disease. Since the early 2000s, there has been a notable increase in BC cases, especially in the cases of localized, early-stage and hormone receptor-positive cancer (44). The immunohistochemical (IHC) analysis of Ki67 is widely recognized as a proliferation marker in BC, offering clinical validity for prognostic evaluations made in stages I and II of the disease (45). Classification of the BC subtype relies heavily on the expression levels of HER2, progesterone receptor (PR) and estrogen receptor (ER) (46). Depending on the subtype, treatment strategies may include chemotherapy, targeted anti-HER2 therapies or endocrine treatments (42). The identification of biomarkers, whether genes, proteins or other types of molecule, is essential: i) For the early detection of the disease; ii) for making an assessment of its severity; and iii) for evaluating the potential treatment responses (47). Consequently, there is an urgent need to discover novel biomarkers that can both improve prognostic accuracy and guide therapeutic decisions.

The amplification, or heightened expression, of the TOP2A gene has been demonstrated to be closely associated with increased tumor aggressiveness, prognostic outcomes and responses to chemotherapy in BC (23,25,28,48). A previous study demonstrated that the amplification of TOP2A is associated with increased tumor size, more advanced stages of cancer, and the presence of erb-b2 receptor tyrosine kinase 2 (ERBB2) positivity, although these traits did not consistently associate with the levels of TOP2A expression (48). Additionally, the expression of the TOP2A gene was found to be increased in cancer subtypes characterized by high proliferation rates, including basal-like, luminal B and HER2-enriched tumors (48). As such, TOP2A expression acts as a proliferative marker, signaling the rapid expansion of these tumor subtypes (48). A subsequent study revealed that elevated TOP2A levels associate with poorer prognoses in patients with luminal BC (28), and the suppression of TOP2A in luminal BC cells leads to reduced cell proliferation. Furthermore, a fluorokinase reporter gene assay has demonstrated that miR-139 targets the 3′-untranslated region (3′-UTR) of TOP2A mRNA, and its overexpression led to a significant reduction in cell proliferation. On the other hand, increasing TOP2A expression was also shown to counteract the effects of miR-139 (28). Triple-negative BC (TNBC) represents the most aggressive subtype of BC, characterized by poor prognosis and a lack of ER, PR and HER2 receptors (49). A previous study demonstrated that a peptide vaccine targeting TOP2A in TNBC is highly immunogenic, inducing a strong immune response, as evidenced by significant reductions in both tumor incidence and the mean tumor volume in mouse models. This vaccine was shown to stimulate tumor-infiltrating lymphocytes through a specific T-cell receptor sequence, offering a novel and effective approach to TNBC prevention and treatment (50).

Differential sensitivity to TOP2 inhibitors, such as anthracyclines, is evident in BC, depending on whether there is amplification or deletion of TOP2A. Amplification of TOP2A results in overexpression of the TOP2A protein, enhancing tumor sensitivity to anthracycline-based treatments, whereas its deletion diminishes TOP2A levels, fostering resistance to these drugs (25,51,52) (Fig. 4).

Additionally, in terms of BC care, co-amplification of the HER2 gene with TOP2A has been shown to have prognostic significance. Both the overall survival (OS) and the progression-free survival (PFS) rates were found to improve in a group of ~5,000 patients with co-amplification of HER2 and TOP2A when administered anthracyclines, either alone or in conjunction with trastuzumab (23). A larger validation study confirmed this association, further supporting the potential of TOP2A amplification as a predictive biomarker for anthracycline-based chemotherapy (23).

LC, known to have the highest mortality rate globally, is typically identified in its advanced stages (53,54). Data from the American Cancer Society have estimated that, in 2024, there will probably be 234,580 new LC cases and 125,070 fatalities resulting from LC, accounting for ~20% of all cancer-associated deaths (44). Lung adenocarcinoma (LUAD), the most common histological subtype, is frequently associated with metastasis and recurrence, thereby contributing to high mortality rates. The failure of therapy in regard to LC is often due to factors such as immune system evasion, resistance to chemotherapy and radiation, and the complexities of tumor heterogeneity, recurrence and metastasis. These factors highlight the urgent need to delineate the pathogenesis of, and the molecular mechanisms underpinning, these tumors to develop innovate targeted therapeutic approaches (55,56).

The p53 protein is instrumental in reducing the rates of tumor cell proliferation and metastasis, and its malfunction is typically associated with LUAD development and progression (57). A previous study demonstrated that silencing TOP2A led to a decrease in the proliferative, migration and invasive capabilities of LUAD cells. On the other hand, TOP2A appears to promote LUAD cell proliferation and metastasis through affecting genes within the p53 pathway, notably cyclin B1 (CCNB1) and CCNB2 (31). The ERK/JNK/p-P38/CHOP signaling pathway, known to be activated under hypoxic conditions, facilitates both LUAD cell proliferation and migration, and the resistance of LUAD cells to apoptosis, as determined by measuring the phosphorylation levels of the various components of the pathway. Du et al (29) reported that reduced TOP2A expression decreases LUAD cell proliferation and increases the rate of apoptosis, with significant upregulation of the levels of phosphorylated (p)-ERK, p-JNK, p-P38 and CHOP proteins in siTOP2A cells. These findings suggested that low levels of TOP2A expression can drive LUAD progression through the ERK/JNK/p-P38/CHOP pathway. Moreover, tumor angiogenesis is critical for tumor growth and proliferation. In non-small cell lung cancer (NSCLC), TOP2A has been shown to encourage vascular mimicry through increasing the levels of Wnt3a, thereby improving tumor cell plasticity and motility. Moreover, TOP2A was shown to increase the expression of programmed death-ligand 1 (PD-L1), which facilitated tumor immune evasion (58). Taken together, these findings have underscored the potential of TOP2A as both a biomarker and a therapeutic target in NSCLC.

Primary liver cancer (PLC) is categorized into three main histological subtypes: Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma and combined hepatocellular-intrahepatic cholangiocarcinoma (59). HCC represents the most prevalent type, constituting 70–85% of all cases of PLC (60,61). The principal risk factor for developing HCC is hepatitis B virus infection (62). The current treatment modalities for HCC include hepatectomy, liver transplantation, ablation, transarterial embolization, radiotherapy and systemic pharmacotherapy (63). Despite improvements that have been made in screening and diagnostic techniques, both the global incidence and cancer-specific mortality of HCC continue to escalate, with patients being predominantly diagnosed at advanced disease stages (64).

TOP2A fulfills a vital role in the pathology of HCC, where its overexpression is associated with enhanced tumor proliferation, metastasis and resistance to chemotherapy (30,65–67). An IHC study of 40 clinically resected HCC samples revealed a marked increase in TOP2A expression in tumor tissues (66). Moreover, array-based transcriptional profiling pinpointed a significant upregulation of TOP2A on chromosome 17q21.2, which mirrored findings identified for other types of cancer, including GC, prostate cancer (PCa) and neuroblastoma, thereby connecting this chromosomal region to tumor progression. A further study linked an increase in TOP2A expression with an earlier onset of HCC, shorter patient survival rates and increased resistance to chemotherapy (68).

The epithelial-mesenchymal transition (EMT) is a crucial process where cells assume multiple somatic cell states, facilitating tumor spread and metastasis. TOP2A is known to increase the expression level of the transcription factor Snail through the phosphorylation of ERK1/2 and SMAD2 (S425/250/255), which subsequently suppresses the expression of E-cadherin and potentially fosters HCC metastasis via the p-ERK1/2/p-SMAD2/Snail pathways (65). Additionally, miR-144-3p, typically under-expressed in HCC, has been shown to inhibit tumor cell proliferation and invasion via interacting with various signaling pathways, including the p53 pathway. Elevated miR-144-3p levels are able to mitigate the adverse effects of anomalous TOP2A expression on HCC cell proliferation, migration and invasion, and also its effects on the EMT process, thereby potentially slowing HCC progression (30). Feng et al (69) demonstrated that TOP2A, through the Hippo-Yes-associated protein (YAP) signaling pathway, is capable of advancing the growth, metastasis and osteoclastogenesis in HCC cells, marking it as a critical gene associated with HCC bone metastasis.

Regorafenib, a multikinase inhibitor that acts on the RAS/RAF/MEK/ERK signaling pathway, is utilized as a second-line treatment for advanced or metastatic HCC. Nevertheless, the emergence of primary or acquired resistance significantly hampers its effectiveness (67,70). The study by Wang et al (67) demonstrated that the suppression of TOP2A is able to alleviate resistance to regorafenib in HCC models, thereby improving therapeutic outcomes, especially when combined with doxorubicin, a well-known TOP2A inhibitor. Considering the crucial function of TOP2A in HCC, focusing attention on this gene may both lead to the identification of novel therapeutic strategies and improve the efficacy of current treatments.

Among the types of cancer-associated death, PC ranks 3rd, with a 5-year OS rate of 9%, declining to a critically low 3% for metastatic cases (71,72). Pancreatic ductal adenocarcinoma (PDAC) is the most common subtype of PC, and >90% of all cases are attributed to this subtype (71). Typically, patients exhibit few clinical signs until the cancer has advanced significantly, resulting in most patients being diagnosed at advanced or metastatic stages due to the inadequacy of early detection methods (73,74). At present, surgical resection is the sole curative therapy available for PC, although enhancements in adjuvant chemotherapy have improved long-term survival rates (75). Therefore, the discovery of novel biomarkers and therapeutic targets remains a critical priority.

The regulation of TOP2A expression in PC involves complex molecular mechanisms that profoundly influence the behavior of the cancer cells (76–78). As a co-activator of β-catenin, TOP2A activates the EMT, thereby facilitating the proliferation and migration of PC cells. miR-139 has been shown to serve as a tumor suppressor, directly targeting TOP2A, thereby decreasing its expression and slowing down the malignant progression of the tumor (76). This underscores the crucial role of the miR-139/TOP2A/β-catenin axis in the aggressive development of PC (76). Additionally, DiGeorge syndrome critical region gene 5 (DGCR5), a long non-coding RNA (lncRNA), has been strongly associated with oncogenesis (79). Liu et al (77) reported that DGCR5 functions as a competitive endogenous RNA, which is acted upon by the transcription factor paired box 5 (PAX5) to modulate TOP2A, thereby activating the Wnt/β-catenin pathway, which promotes the advancement of PC via capturing miR-3163. In addition, TOP2A and its transcriptional activators, specificity protein 1 (SP1) and high-mobility group protein B2 (HMGB2), have been found to be overexpressed in clinical samples of PDAC. In PDAC cells, a number of transcriptional regulators work together to promote TOP2A expression. Combination treatment studies have shown that TOP2A knockdown increases the susceptibility of PDAC cells to the chemotherapeutic medication cisplatin (78), and TOP2A knockdown in PDAC cells reduces cell proliferation, migration and invasion.

As the 3rd leading cause of cancer-associated deaths worldwide, and the 5th most common malignant tumor overall, GC poses an enormous public health problem globally (80). Helicobacter pylori infection greatly increases the likelihood of developing GC (81). Although surgical resection typically provides a relatively favorable prognosis for those diagnosed at the early stages, the often-vague initial symptoms of the disease lead to numerous patients being diagnosed at later stages, thereby reducing the effectiveness of surgical interventions and yielding a median OS rate of only 12 months (82). Therefore, the discovery of early biomarkers is critical to enable the prompt diagnosis of GC, to customize treatment strategies, and to enhance outcomes for patients with GC.

Significant overexpression of TOP2A and E2F transcription factor 1 (E2F1) has been observed in GC tissues. Studies have revealed that E2F1 is able to bind to the promoter region of TOP2A in different types of GC. In a study by Chen et al (83), in vitro analyses confirmed that the activation of TOP2A by E2F1 led to increases in GC cell viability, migration and invasion, whereas apoptosis was inhibited. lncRNAs, defined as non-coding RNAs exceeding 200 nucleotides in length, are instrumental in cancer dynamics, as they operate through modifying gene expression profiles within the transcriptome (84). Cui et al (85) demonstrated that overexpression of the lncRNA FAM230B reduces the level of miR-27a-5p in GC cells, which consequently leads to a reduction in the rates of cell proliferation, migration and invasion, and an increase in the extent of apoptosis due to a lowering of TOP2A expression. These findings suggested that lncRNA FAM230B may promote the growth and spread of GC through capturing miR-27a-5p, thereby increasing TOP2A expression. Targeting FAM230B or modulating miR-27a-5p expression could therefore provide a strategy to inhibit the upregulation of TOP2A, thereby potentially impeding tumor growth and metastasis.

CRC is a leading gastrointestinal malignancy worldwide, currently ranked 3rd among all cancers, and 2nd in terms of cancer-associated mortality (61). Projections for 2024 estimate that 152,810 individuals will be diagnosed with CRC, resulting in 53,010 deaths. Notably, CRC is the principal cause of cancer-associated mortality in men under the age of 50 (44). Both colon cancer and rectal cancer (RC) are categorized as subtypes of CRC, and most of the research efforts up to this point have been concerned with treating these entities collectively (86). Detection of DNA methylation levels using methylation-specific PCR is an essential early screening method for CRC, as this targets highly specific genes, including Septin9, ALX homeobox 4 (AXL4) and syndecan-2 (SDC2). This approach allows for the enhanced sensitivity of the assay through integrating the methylation status of these genes, which reflect multiple molecular pathways of tumorigenesis (87). Surgical resection offers a potentially curative option, although immunotherapy, targeted therapy and radiotherapy are also beneficial in metastatic cases. High rates of incidence and chemoresistance are major factors contributing to recurrence and poor prognosis in CRC, especially in China (88). Targeted pharmacological interventions aimed at specific signaling pathways are pivotal for enhancing treatment efficacy and reducing resistance.

In colon cancer cells, the knockdown of TOP2A has been shown to decrease cell proliferation and invasion, whereas apoptosis was promoted. Western blot assay experiments have revealed that knocking down TOP2A affects the levels of apoptosis-associated proteins (Bcl-2 and Bax) and invasion-associated proteins [matrix metalloproteinase (MMP)-2 and MMP-9], as well as diminishing the phosphorylation levels of ERK and AKT. Therefore, overexpressing TOP2A serves as a key upstream regulator that anomalously activates proliferative signaling in colon cancer cells (89).

A study by Carvalho et al (90) demonstrated that inhibitors of TOP2A, such as doxorubicin and mitoxantrone (MTX), effectively alter gene expression profiles in RC, thereby inhibiting cell proliferation. Furthermore, their therapeutic efficacy was shown to be associated with the integration of gene expression signatures from patients with RC with those induced by these drugs. The study also noted a significant association between the gene dosage or levels of TOP2A and the sensitivity towards these inhibitors. In addition, CRISPR-Cas9 and shRNA loss-of-function analyses were performed, which confirmed that a reduction in TOP2A expression leads to a significant reduction in cell proliferation, with increased TOP2A expression commonly observed in RC samples, underscoring its therapeutic potential and supporting personalized treatment strategies based on TOP2 inhibitors.

Significant overexpression of TOP2A in parental CRC cell lines has shown that TOP2A overexpression confers greater resistance to chemotherapy agents such as irinotecan (targeting TOP1) and etoposide (targeting TOP2), probably as a result of the inhibition of apoptosis (91). Additionally, combination chemotherapy involving oxaliplatin, which is commonly to treat both advanced and metastatic CRC, has encountered resistance issues. Up-frameshift protein 1 (UPF1), an mRNA surveillance factor, has been identified as a promoter of oxaliplatin resistance (88). Intriguingly, in a study by Zhu et al (88), silencing TOP2A in these experiments negated UPF1-mediated oxaliplatin resistance, suggesting that TOP2A may contribute to UPF1-induced resistance mechanisms. Furthermore, resistance to treatment in CRC is shaped by cancer stem cell (CSC)-like stemness characteristics, which are enhanced following the upregulation of UPF1. The increase in UPF1-induced stemness characteristics could be partially reduced through silencing the expression of TOP2A, suggesting that UPF1 may sustain CSC-like stemness through a TOP2A-dependent pathway. Consequently, both current research and clinical trials that are in progress have underscored the significant potential and clinical importance of TOP2A in the diagnosis and treatment of CRC (88). Therefore, targeting TOP2A expression may offer a novel therapeutic strategy for patients with oxaliplatin-resistant CRC.

Among all cancers, CC ranks 4th in prevalence worldwide. With a death rate of 3.42 per 100,000 women, it affects 11.35 per 100,000 women in China (92). A major factor in the progression of this disease is the ongoing production of the viral oncogenes Early Protein 6 (E6) and Early Protein 7 (E7), which originate from high-risk strains of human papillomavirus (HPV) (93). DNA methylation testing is an important aspect of CC screening, especially in the case of women who have tested positive for HPV. For example, the WID-qCIN test is able to detect cervical precancerous lesions by assessing the DNA methylation status of the DPP6, RALYL and GSX1 genes. This technique, combined with HPV16/18 genotyping, significantly improves the ability to predict precancerous conditions (94). However, in spite of effective screening and vaccination programs, the mortality rate for advanced CC remains high, underscoring the limitations of current treatment strategies for the cancer in its advanced stages (95).

Numerous studies have reported on the overexpression of TOP2A and its associated oncogenic signaling in CC (96–98). An analysis of three raw microarray datasets from the Gene Expression Omnibus highlighted that TOP2A serves as a potential oncogene and prognostic marker in CC (96). In CC tissues, a significant upregulation of TOP2A was identified compared with the surrounding non-malignant tissues. Via stimulation of the PI3K/AKT pathway, this overexpression of TOP2A may facilitate the migration and invasion of CC cells, enabling them to undergo EMT (97). In addition, a dual-luciferase reporter gene test demonstrated that miR-320a targets the 3′-UTR of TOP2A mRNA, and it has been shown that HPV16 E6 causes a downregulation of miR-320a, which, in turn, increases the migration, invasion and proliferation rates of CC cells. The study by Zhang et al (98) has highlighted the importance of the HPV16 E6/miR-320a/TOP2A axis in the development of CC, suggesting that it may act as a novel therapeutic target through reducing HPV16 E6-induced cellular activity and increasing the extent of apoptosis. In addition, the association of Centromere Protein F, which has a vital role in chromosome segregation during cell division (99), with DNA TOP2A has been found to have synergistic effects in CC. Both proteins, significantly upregulated in CC tissues, cause the activation of genes that are associated with the cell cycle and DNA repair, linking their high expression to tumor metastasis and specific somatic mutations in genes such as TP53, MSH2 and RB1, thereby affirming their significance in cancer biology research (99).

OC ranks as the most lethal of gynecological cancers due to its insidious development and the lack of early detection techniques, leading to late-stage diagnoses in the majority of cases. While initial chemotherapy results in remission for ~80% of affected individuals, the 5-year survival rates for patients with this cancer in its advanced stages are still discouragingly low, a consequence of significant tumor diversity and prevalent resistance to chemotherapy (100,101). Consequently, it is crucial to enhance our understanding of the pathophysiology of OC and to discover novel therapeutic targets to improve the clinical outcomes for these patients.

In OC, the intricate expression patterns of TOP2A, especially between initial and subsequent occurrences, have suggested a strong link exists between the efficacy of, and resistance to, chemotherapy (102,103). A previous study showed a heightened presence of TOP2A in tumor cells compared with adjacent stromal cells at both the protein and the mRNA level. A notable variation was observed in cases of recurrent OC where the patients were subjected to platinum-based therapies, and a reduction in TOP2A expression was noted in the epithelial cells of the tumors. By contrast, in recurrent tumors treated with carboplatin, an upsurge in TOP2A expression was identified within stromal cells adjacent to the tumors compared with primary cases (102). Similarly, IHC analysis across 50 cases of OC revealed that the levels of TOP2A and HER2 were increased in the epithelial cells of primary tumors, whereas these levels were decreased in recurrent forms of the disease, which conversely showed increased levels of TOP2A expression in the stromal cells post-platinum therapy. Hence, integrating TOP2A inhibitors with a platinum-based treatment protocol could potentially increase chemotherapy sensitivity, and reduce resistance in recurrent OC. Assessing TOP2A levels in both the tumor and the surrounding stromal cells is essential for predicting chemotherapy outcomes (103).

TOP2A has been identified as a pivotal factor in the proliferation of OC cells, where reducing its expression has been shown to inhibit cell proliferation, triggering G1-phase arrest, and thereby promoting cell death. In-depth in vitro studies have revealed that TOP2A subsequently influences the activity of transcription factors, such as c-Myc and the cyclin D1/cyclin-dependent kinase 4 (CDK4) complex, through the AKT/mTOR pathway, ultimately stimulating the proliferation of OC cells (104). Therefore, TOP2A has a crucial role in regulating the AKT/mTOR pathway, and inhibiting its expression could significantly reduce the pathway's function, thereby restraining the progression of ovarian tumors (104).

RCC originates from the renal cortex, and is identified as the 9th most prevalent cancer among men, and the 14th among women (105,106). The most common subtype, clear cell RCC (ccRCC), constitutes over 75% of all RCC cases, and is distinguished by its pronounced aggressiveness and poor prognosis (107,108). In total, ~40% of individuals with ccRCC eventually develop metastases, resulting in a dismal 5-year survival rate of only 10% (109,110). Therefore, in order to enhance the prognosis and quality of life for patients with RCC, the identification of new treatment targets and diagnostic indicators is urgently required.

The expression of TOP2A is markedly greater in RCC tissues and cell lines compared with normal cell lines and the neighboring non-cancerous tissues. Furthermore, TOP2A knockdown has been shown to lead to a significant decrease in RCC cell proliferation, with a concomitant increase in apoptosis (111). Similarly to TOP2A, miR-30c-2-3p has been shown to regulate RCC cell proliferation, thereby promoting apoptosis through activating the Fas/FasL/caspase-8/caspase-3 pathway (111). Furthermore, ccRCC tissues were found to have elevated levels of short nucleolar RNA host gene 3 (SNHG3), which performs a role in the progression of the cancer through interacting with miR-139-5p to increase TOP2A expression. Taken together, these findings have highlighted the importance of the SNHG3/miR-139-5p/TOP2A axis in the development of ccRCC (112).

Parker et al (113) investigated TOP2A expression in ccRCC, and sought to determine how it correlates with the likelihood of death from cancer. In individuals with low-risk diseases, where the mortality risk is ~3-fold higher compared with those with lower TOP2A expression, the data revealed that high levels of TOP2A are closely associated with an increased risk of cancer-specific death. This correlation has been validated across two independent cohort studies, affirming the significant prognostic utility of TOP2A following multivariate adjustments, which has highlighted its importance as a biomarker for postoperative monitoring in patients with ccRCC. According to Wang et al (114), responses to immune checkpoint inhibitor therapy vary significantly among patients with kidney renal clear cell carcinoma (KIRC). Tumors categorized within the high programmed cell death (PCD) subtype exhibit an immunosuppressive phenotype with a notable influx of regulatory T cells and tumor-associated macrophages, whereas those in the low PCD subtype respond more favorably to anti-programmed death-1 (anti-PD-1) medications. A prognostic model employing 13 PCD genes pinpointed TOP2A as a pivotal gene within this framework; its inhibition was shown to significantly impede the growth and movement of KIRC cells, emphasizing its integral role in tumoral advancement (114). Elucidating the molecular mechanisms underlying TOP2A dysregulation, and the implications of its dysregulation in KIRC, are pivotal for the development of more effective therapies.

BLCA originates from the mucosa of the bladder, and is one of the most common and most lethal malignancies within the genitourinary system. The lack of specific diagnostic and therapeutic measures often leads to diagnosis at advanced stages, which predisposes patients to metastasis and poor outcomes (115–118). Previous studies have highlighted the diverse functions of TOP2A in BLCA, pointing to its potential as a target for therapy (119–121).

Genetic modifications in TOP2A in BLCA typically manifest as gene amplification and protein overexpression, exacerbating the malignant traits of BLCA cells and increasing their responsiveness to specific chemotherapeutic drugs. Results from an examination of 2,317 bladder tumor samples using fluorescence in situ hybridization (FISH) and IHC analyses revealed that, in muscle-invasive variants of the disease, the amplification and overexpression of TOP2A was associated with reduced survival rates. Additionally, HER2 amplification, occurring alongside TOP2A genomic changes in ~50% of these cases, suggested a common association between HER2 and TOP2A genomic alterations in BLCA (119). The gene amplification status within the 17q12-q21 chromosomal region may have clinical implications for predicting the efficacy of targeted therapies against HER2 or TOP2A (119). An increased expression of TOP2A was found to significantly enhance BLCA cell viability, migration and invasiveness. miR-599, which is markedly suppressed in BLCA, acts as an oncogenic regulator by targeting TOP2A directly (120). Similarly, Zeng et al (121) observed that the downregulation of TOP2A substantially reduced the migration and invasion of BLCA cells, promoted apoptosis, and contributed to adriamycin resistance. Given the complexity of factors that influence the responsiveness of BLCA cells to adriamycin, assessing the sensitivity to this type of chemotherapy requires a multifaceted approach that includes multiple biomarkers, not merely TOP2A expression levels alone.

PCa is a neoplastic growth that arises within the epithelial tissue of the prostate gland. It stands as the 2nd most common cancer affecting males globally, and has been identified as the 6th leading cause of mortality among men (122,123). The incidence of PCa has been increasing by ~3% annually since 2014, with diagnoses of regional and distant metastases rising at a rate of ~4.5% per year (44). The Gleason score, a critical grading system derived from the histological evaluation of prostate tissue, measures the degree of aggressiveness of PCa. Higher Gleason scores are indicative of severe cellular abnormalities and dysfunctions that drive the progression of the disease (124). The levels of prostate-specific antigen (PSA) are tightly associated with the progression of PCa, establishing PSA as an essential biomarker for early detection (125). Although a range of treatments for PCa are available, traditional approaches often lead to severe side effects that may contribute to resistance to therapy as the disease progresses (126).

In their study using tissue microarray constructs, Murphy et al (127) noted minimal levels of TOP2A gene amplification in PCa. Their multivariate analysis demonstrated that an increased protein level of TOP2A is associated with unfavorable clinical outcomes, such as advanced disease stages, high Gleason scores, HER2 amplification, androgen resistance and lower survival rates. Furthermore, increased expression levels of the TOP2A protein have been associated with higher Gleason scores and elevated preoperative PSA levels. A comprehensive study utilizing biochemical and pathological data from 193 patients with PCa, examined through IHC and FISH analyses, demonstrated that an increased expression of TOP2A was correlated with reduced biochemical recurrence-free survival, highlighting the importance of TOP2A protein assessment in prognostic evaluations (128). Furthermore, a study by Huang et al (129) demonstrated that the tumor suppressor miRNA-145-5p is downregulated in PCa tissues, whereas the mRNA and protein levels of TOP2A are markedly higher in these tissues compared with non-cancerous ones. Protein-protein interaction analysis revealed TOP2A to be a potential target of miRNA-145-5p, highlighting a significant inverse association between their expression levels in both localized and metastatic PCa settings. These findings, however, still require further experimental validation.