Milk fat globule-EGF factor 8 enhances the proliferation and migration of thyroid carcinoma cells through epithelial-mesenchymal transition and PI3K/AKT signaling pathway.

BACKGROUND: Milk fat globule-EGF factor 8 (MFG-E8) has been found to be involved in the development and progression of several carcinomas. However, the role of MFG-E8 in thyroid carcinoma has not been studied yet. This study aimed to investigate the expression and function of MFG-E8 in thyroid carcinoma (TC).

METHODS: Single-cell RNA sequencing, transcriptome sequencing, mass spectrometry, and immunohistochemistry were used to analyze MFG-E8 expression in papillary thyroid carcinoma (PTC). Western blotting and RT-PCR were performed to assess MFG-E8 expression in TC cell lines. Stable MFG-E8 knockdown cell lines were established, and functional assays were conducted to evaluate the effects of MFG-E8 on TC cell proliferation, migration, and invasion. Bioinformatics analysis and Western blotting were employed to explore the potential downstream signaling pathways. The association between MFG-E8 expression and immune cell infiltration in the tumor microenvironment was also analyzed using bioinformatics tools.

RESULTS: MFG-E8 expression was significantly upregulated in PTC tumor tissues. It was closely associated with specific PTC subtypes, with higher expression observed in the tall-cell subtype compared to the classic and follicular subtypes. Knockdown of MFG-E8 significantly inhibited TC cell proliferation, migration, and invasion. Mechanistically, MFG-E8 was found to be associated with the regulation of epithelial-mesenchymal transition (EMT)-related processes and linked to the modulation of the PI3K/AKT signaling pathway in TC cells. Furthermore, MFG-E8 correlated with the formation of an immunosuppressive tumor microenvironment by modulating immune cell infiltration and activating the PI3K/AKT pathway in immune cells.

CONCLUSIONS: Our findings identify MFG-E8 as a key driver of thyroid carcinoma progression, particularly in aggressive subtypes, and highlight its translational value as a prognostic biomarker and promising therapeutic target by targeting the MFG-E8-PI3K/AKT-EMT axis-providing a new clinical framework for personalized treatment of TC.