Investigating the Role of MAPK۱۲ as a Modulator of VEGF in Pulmonary Alveolar Cells in Stage I Lung Adenocarcinoma

Introduction Lung adenocarcinoma (LUAD), a major subtype of non-small cell lung cancer (NSCLC), is the leading cause of cancer-related deaths in the United States. Its cellular heterogeneity and complex tumor microenvironment (TME) pose significant challenges to treatment. This study explores the role of MAPK۱۲, a differentially expressed gene (DEG), as a potential modulator of Vascular Endothelial Growth Factor (VEGF) in pulmonary alveolar type ۱ (AT۱) and type ۲ (AT۲) cells—key cell types involved in stage I lung adenocarcinoma. MAPK۱۲, part of the p۳۸ MAPK signaling pathway, influences processes like inflammation, apoptosis, and angiogenesis. p۳۸ MAPK signaling activation promotes an inflammatory TME and angiogenesis, crucial for tumor growth and metastasis. VEGF, overexpressed in NSCLC, is a major angiogenic factor that plays a pivotal role in tumor angiogenesis and immunosuppression, promoting an immune-suppressive environment that facilitates tumor progression. This study uses single-cell RNA sequencing (scRNA-seq) and data from the GSE۱۳۱۹۰۷ dataset to identify MAPK۱۲ as a potential therapeutic target in LUAD. Methods scRNA-seq allows for high-resolution analysis of cellular heterogeneity, revealing distinct cell populations and their gene expression profiles. The GSE۱۳۱۹۰۷ dataset, comprising scRNA-seq profiles of ۲۰۸,۵۰۶ cells from ۵۸ LUAD samples derived from ۴۴ patients, serves as the primary resource. A subset of this dataset, comprising four stage I of LUAD samples and four normal lung tissue samples, underwent quality control and integration using the Seurat and Harmony R packages. Cell population annotation was performed using ScType and SingleR packages. Seurat’s FindMarkers function was used to identify markers related to tumor progression and differentially expressed genes. Gene expression analysis highlighted significant heterogeneity in the TME, with specific focus on T cells, alveolar macrophages, NK cells, AT۲ cells, B cells, cancer stem cells, fibroblasts, AT۱ cells, endothelial cells, and ciliated cells. Comparison of differentially expressed genes from VEGF (obtained via KEGG database) and stage I LUAD cells revealed MAPK۱۲ as a gene with increased expression in both AT۱ and AT۲ cancer cells, suggesting its potential role in VEGF modulation and lung adenocarcinoma pathogenesis. Results This study identifies MAPK۱۲ as a potential contributor to VEGF-mediated tumor progression in stage I LUAD. Its elevated expression in AT۱ and AT۲ cells underscores its role in tumorigenesis and highlights its potential as a therapeutic target. Conclusion Our findings offer novel insights into the role of MAPK۱۲ as a modulator of VEGF in AT۱ and AT۲ cells in early-stage LUAD. The study highlights the interplay between MAPK۱۲ signaling, VEGF-driven angiogenesis, and the TME, offering promising avenues for targeted therapies aimed at disrupting these interactions to improve patient outcomes. Future research should explore the clinical implications of targeting MAPK۱۲ in NSCLC treatment.

کلیدواژه ها:

MAPK۱۲ ، VEGF modulation ، Stage I Lung Adenocarcinoma ، Single-cell RNA sequencing ، Tumor microenvironment