The role of TOP2A in immunotherapy and vasculogenic mimicry in non-small cell lung cancer and its potential mechanism

Abstract

Type IIA topoisomerase (TOP2A) is significantly associated with malignant tumor development, invasion, treatment and its prognosis, and has been shown to be a therapeutic target against cancer. In contrast, the role of TOP2A in the immunotherapy of non-small cell lung cancer as well as in Vasculogenic mimicry (VM) formation and its potential mechanisms are unclear. The aim of this study was to investigate the role of TOP2A in proliferation, skeleton regulation, motility and VM production in non-small cell lung cancer and its mechanisms by using bioinformatics tools and molecular biology experiments. Subgroup analysis showed that the low-risk group had a better prognosis, while the high-risk group was positively correlated with high tumor mutational load, M1-type macrophage infiltration, immune checkpoint molecule expression, and immunotherapy efficacy. As confirmed by further clinical specimens, the presence of TOP2A and VM was significantly and positively correlated with poor prognosis. Our study established a model based on significant co-expression of TOP2A genes, which significantly correlated with mutational load and immunotherapy outcomes in patients with non-small cell lung cancer. Further mechanistic exploration suggests that TOP2A plays an important role in immunotherapy and VM formation in NSCLC through upregulation of Wnt3a and PD-L1 expression.

Anti-cancer effects of Coix seed extract through KCTD9-mediated ubiquitination of TOP2A in lung adenocarcinoma

“…showed that TOP2A positivity was associated with PD-L1 expression in NSCLC ( p < 0.001) [ 28 ]. TOP2A has been recently revealed to play an important role in immunotherapy and vasculogenic mimicry formation in NSCLC through the upregulation of PD‑L1 expression [ 29 ]. In the present study, we revealed that the knockdown of TOP2A again overturned the impact of sh-KCTD9 on the CD8 + cells and PD-L1 expression.…”

Identification of hub genes and pathways in hepatitis B virus‐associated hepatocellular carcinoma: A comprehensive in silico study

“…In addition, high levels of TOP2A have been linked to more aggressive tumor behavior and later disease stages in several types of cancer such as HCC, 38 breast cancer, 36 and NSCLC 39 . Furthermore, upregulation of TOP2A is associated with a negative prognosis, increased tumor grades, and stages, suggesting its involvement in cancer aggressiveness 39,40 . Notably, chemotherapy that targets TOP2 enzymes, such as TOP2A, is often used to treat both solid tumors and blood cancers 40 .…”

“… 39 Furthermore, upregulation of TOP2A is associated with a negative prognosis, increased tumor grades, and stages, suggesting its involvement in cancer aggressiveness. 39 , 40 Notably, chemotherapy that targets TOP2 enzymes, such as TOP2A, is often used to treat both solid tumors and blood cancers. 40 However, the effectiveness of TOP2 inhibitors as primary chemotherapeutic agents is counteracted by the potential for secondary cancers and heart damage, underscoring the need for more accurate targeted approaches.…”

“… 39 , 40 Notably, chemotherapy that targets TOP2 enzymes, such as TOP2A, is often used to treat both solid tumors and blood cancers. 40 However, the effectiveness of TOP2 inhibitors as primary chemotherapeutic agents is counteracted by the potential for secondary cancers and heart damage, underscoring the need for more accurate targeted approaches. 41 , 42 Research indicates that TOP2A might serve as a novel prognostic biomarker and therapeutic target for HCC.…”

Different Mechanisms in Doxorubicin-Induced Cardiomyopathy: Impact of BRCA1 and BRCA2 Mutations

“…ECs express both TopoIIa and IIb as they are proliferative in comparison to terminally differentiated non-proliferative cardiomyocytes, especially during stress-induced endothelial activation, wound healing, and angiogenesis [113]. Therefore, they are more vulnerable to Dox-inhibition of TopoII in addition to Dox-induced DNA intercalation and micronuclei generation.…”