TGFBR3 regulates the expression of FATP2-ACSL1 axis related proteins and accompanies changes in the migration and invasion ability of lung cancer cells

Abstract

Background Abnormal lipid metabolism promotes lung cancer progression. This study explores how TGFBR3 regulates fatty-acid-metabolism-related protein expression via the FATP2-ACSL1 axis to suppress lung cancer invasion and metastasis, and preliminarily assesses the potential clinical value of TGFBR3 and FATP2. Methods Serum samples were collected from 30 healthy individuals and 170 newly diagnosed lung cancer patients for lipid profiling. Network pharmacology, Mendelian randomization, molecular docking, co-immunoprecipitation (Co-IP) and GST-Pull down assay were used to validate the TGFBR3-FATP2 interaction. Stable cell lines were established to assess function and mechanism via CCK-8, wound healing, Transwell, and Western blotting. Serum levels of soluble TGFBR3 (sTGFBR3) and FATP2 were measured by ELISA. Results Serum CHOL, HDL-C, and LDL-C were significantly decreased in lung cancer patients (P < 0.05). Mendelian randomization indicated that elevated HDL-C reduces lung cancer risk (OR = 0.5607). Molecular docking showed a binding energy of −12.5 kcal/mol, Co-IP and GST-Pull down assay confirmed the interaction. TGFBR3 overexpression inhibited migration and invasion, while knockdown had the opposite effect (P < 0.05). TGFBR3 regulated FATP2, ACC1, ACSL1, and SCD1 expression but not CD36. Lipofermata reversed the protein changes induced by TGFBR3 knockdown. ELISA results showed that serum sTGFBR3 and FATP2 levels were significantly higher in lung cancer patients than in healthy and pneumonia controls (P < 0.05), and sTGFBR3 levels were higher in LUSC and SCLC than in LUAD (P < 0.05). The AUCs were 0.931 for sTGFBR3 and 0.998 for FATP2, showing higher diagnostic performance compared with CEA and other traditional markers in this cohort. Furthermore, sTGFBR3 levels decreased after carboplatin dose reduction or discontinuation and increased after treatment resumption; in vitro experiments confirmed that carboplatin upregulated TGFBR3 expression and promoted the release of its soluble form (P < 0.05). although this effect may be partly attributed to nonspecific cell injury. Conclusions TGFBR3 interacts with FATP2 and is associated with the regulation of migration and invasion in lung cancer cells, potentially involving the FATP2-ACSL1 axis. Additionally, serum levels of sTGFBR3 and FATP2 were identified as potential candidate biomarkers for lung cancer, warranting further validation in independent cohorts migration.