PPARG-FABP4 regulates PI3K/Akt pathway to promote lung cancer-associated macrophage endoplasmic reticulum stress-mediated CD36 expression and affects lung squamous cell carcinoma metastasis.

[BACKGROUND] Lung squamous cell carcinoma (LUSC) is a common subtype of primary lung cancer. Macrophage endoplasmic reticulum stress (ERS) is crucial in regulating lung cancer metastasis. Here, effects of Fatty acid binding protein 4 (FABP4) on macrophage ERS and lung cancer metastasis were evaluated.

[METHODS] First, we used CancerSCEM single cell database to analyze interaction between tumor cells in LUSC and various immune cells in surrounding microenvironment. Database of The Cancer GenomeAtlas (TCGA) was utilized to analyze variations in mRNA expression and conduct survival analysis within lung cancer tissues. Then, 42 samples of LUSC tissue and corresponding adjacent normal tissues were obtained from patients. IHC staining evaluated FABP4 expression and co-localization with CD163. Lipid metabolic changes in macrophages were evaluated utilizing immunofluorescence and oil red O staining. Lung cancer cells (H520) were co-cultured with primary macrophages from lung cancer patients, and H520 cell proliferation, migration and invasion were detected. ChIP and dual luciferase reporter assays validated direct binding between peroxisome proliferator-activated receptor gamma (PPARG) and FABP4. Subcutaneous and metastatic tumor models were set up to confirm FABP4's impact on lung cancer progression in vivo.

[RESULTS] FABP4 expression was upregulated in macrophages near cancer sites but declined in LUSC cancer epithelial cells. Silencing FABP4 in primary macrophages from lung cancer patients suppressed lipid metabolism in macrophages, reducing macrophage ERS and hindering lung cancer cell metastasis. PPARG enhanced FABP4 expression at the transcriptional level. PPARG-FABP4 controlled PI3K/Akt pathway, promoting ERS-induced CD36 expression in lung cancer-related macrophages, impacting lung cancer metastasis. Deleting macrophage FABP4 impaired both proliferation and metastasis of lung cancer in mice.

[CONCLUSION] PPARG regulates FABP4 mRNA transcription, initiating macrophage ERS through PI3K/Akt-mediated lipid metabolism, thus modulating macrophage CD36 levels and influencing lung cancer metastasis.