TFAP2A regulates SGPP2 transcription to promote lipid accumulation and activate the Wnt/β-catenin signaling pathway to promote malignant progression in lung adenocarcinoma

Lung adenocarcinoma (LUAD) is the leading cause of cancer-related mortality worldwide, highlighting the urgent need for additional molecular biomarkers and therapeutic targets. Transcription factor AP-2α (TFAP2A) is highly expressed in LUAD and is associated with poor prognosis. Sphingosine-1-phosphate phosphatae 2 (SGPP2/SPP2) has been implicated in tumor progression in multiple cancer types; however, its functional role in LUAD cells and the underlying mechanisms remain unclear. Bioinformatics analysis was conducted to elucidate the expression patterns of SGPP2 and TFAP2A. Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB), and immunohistochemistry (IHC) were performed to measure mRNA and protein expression levels. Cellular proliferation and cell cycle progression were evaluated using the Cell Counting Kit-8 (CCK-8) assay, 5-ethynyl-2’-deoxyuridine (EdU) assay, colony formation assay, and flow cytometry. Migratory and invasive capabilities were evaluated using transwell and wound-healing assays. Lipid metabolism was assessed by measuring triglyceride (TG) and total cholesterol (TC) levels, using Oil Red O and Nile Red fluorescence staining. The regulatory relationship between TFAP2A and the SGPP2 promoter was confirmed using chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. Protein-protein interactions were investigated using co-immunoprecipitation (CoIP) assay. The in vivo tumorigenic potential was examined using a xenograft model in nude mice. SGPP2 and TFAP2A were upregulated in LUAD. High SGPP2 expression is closely associated with lymph node metastasis. Functional experiments demonstrated that SGPP2 promotes LUAD cell proliferation, migration, and epithelial-mesenchymal transition (EMT). Under physiological conditions, TFAP2A transcriptionally activates SGPP2 in LUAD cells, whereas SGPP2 reciprocally inhibits TFAP2A expression. Downstream pathway analysis revealed that SGPP2 overexpression downregulated SGPP1 expression, leading to increased sphingosine-1-phosphate (S1P) levels in the cells. This, in turn, promotes intracellular lipid accumulation and phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser9, thereby facilitating the nuclear translocation of β-catenin. Consequently, CyclinD1 expression is upregulated, ultimately driving LUAD progression. SGPP2 and TFAP2A are highly expressed in LUAD. SGPP2, which regulates S1P levels and is transactivated by TFAP2A, promotes lipid accumulation and activates the Wnt/β-catenin signaling pathway to facilitate the progression of lung adenocarcinoma.