RUNX1-BMP2 Promotes Vasculogenic mimicry in Laryngeal Squamous Cell Carcinoma via Activation of the PI3K-AKT Signalling Pathway

Abstract

Abstract Background Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck. Vasculogenic mimicry (VM) refers to fluid channels formed by invasive tumour cells rather than endothelial cells and is crucial for tumour growth and metastasis. However, the regulatory mechanisms underlying VM during the malignant progression of LSCC remain largely unknown.Methods Gene expression and clinical data for LSCC were sourced from the TCGA and Gene GEO (GSE27020) databases. A risk prediction model associated with VM was established using LASSO and COX regression analyses. Based on their risk scores, patients with LSCC were categorised into high- and low-risk groups. The disparities in immune infiltration, tumor mutational burden (TMB), and functional enrichment between these two groups were examined. The identification of core genes in LSCC was conducted using the machine learning (SVM-RFE) and the WGCNA algorithm. Subsequently, the involvement of Bone Morphogenetic Protein 2 (BMP2) in VM and metastasis was investigated both in vitro and in vivo. To elucidate the downstream signaling pathways regulated by BMP2, Western blot experiments were performed. Additionally, ChIP experiments were employed to identify the key transcription factors responsible for modulating BMP2 expression.Results We established a new precise prognostic model for LSCC related to VM based on three genes: BMP2, EPO, and AGPS. The ROC curves from both TCGA and GSE27020 validation cohorts demonstrated precision survival prediction capabilities, with the nomogram showing some net clinical benefit. Multiple algorithm analyses indicated that BMP2 was a potential core gene. Further experimental results suggested that BMP2 promotes VM and metastasis in LSCC. The malignant progression of LSCC is promoted by BMP2 via the activation of PI3K-AKT signalling pathway, and the high expression of BMP2 in LSCC was a result of its transcriptional activation by runt-related transcription factor 1 (RUNX1).Conclusion BMP2 predicts poor prognosis in LSCC, promotes LSCC VM and metastasis through the PI3K-AKT signalling pathway, and is transcriptionally regulated by RUNX1. BMP2 may be a novel, precise diagnostic, and therapeutic biomarker for LSCC.