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

Abstract

Background: 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 VM formation and its potential mechanisms are unclear. Methods: Based on the 82 significantly co-expressed genes of TOP2A screened, consensus molecular typing was performed by the NMF algorithm, and the effect of immunotherapy was further evaluated in two groups of patients with high and low risk. The expression of TOP2A and VM in non-small cell lung cancer tissues was assessed by immunohistochemistry. Western Blot, colony formation assay, CCK8 assay, cell cycle and apoptosis assay, tube-forming assay and cytoskeleton staining were used to verify the role of TOP2A in proliferation, skeleton regulation, motility and VM generation in non-small cell lung cancer and its mechanism. Results: Patients with lung adenocarcinoma were distinguished into high- and low-risk subgroups based on significant co-expression of TOP2A genes. Subgroup analysis showed that patients in the low-risk group had a better prognosis, while higher risk was associated with higher tumor mutational load, M1-type macrophage and immune checkpoint molecule expression. The Tumor Immune Dysfunction and Rejection (TIDE) and Tumor Immunome Atlas (TCIA) databases also showed significant differences in the outcome of immunotherapy in patients with different types of lung adenocarcinoma. As verified by further clinical specimens, the presence of both TOP2A and VM were significantly and positively correlated with poor prognosis. TOP2A may ultimately affect immunotherapy and VM formation in non-small cell lung cancer through its involvement in regulating the expression of Wnt3a and PD-L1. Conclusion: A model based on significantly co-expressed genes of TOP2A was significantly correlated with mutational load and immunotherapeutic effects in patients with non-small cell lung cancer. TOP2A plays an important role in immunotherapy and VM formation in non-small cell lung cancer through upregulation of Wnt3a 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.…”