Interleukin-27 promotes oral squamous cell carcinoma pathogenesis via FSIP1-mediated activation of the PI3K-Akt signaling pathway.

OBJECTIVE: This study aimed to examine the mechanisms by which Interleukin-27 (IL-27) contributes to the pathogenesis of oral squamous cell carcinoma (OSCC) through focal adhesion-induced stemness protein 1 (FSIP1)-mediated activation of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signaling pathway.

METHODS: The effects of IL-27 on cellular proliferation, apoptosis, and migration were examined in human OSCC cell lines [squamous cell carcinoma cell line-27 (CAL-27) and squamous cell carcinoma-4 (SCC-4)] using Cell Counting Kit-8 (CCK-8) assays, flow cytometry, and wound healing assays. Western blot (WB) analysis was performed to determine the expression of epithelial-mesenchymal transition (EMT) markers. High-throughput sequencing was used to identify differentially expressed genes and enriched pathways, while quantitative Polymerase Chain Reaction (qPCR) and WB validated the expression of FSIP1 and PI3K-Akt pathway-related proteins. An oral carcinogenesis mouse model was established using 4-nitroquinoline-1-oxide (4NQO). Following IL-27 treatment, histopathological alterations in tongue tissue were examined with Hematoxylin-Eosin (HE) staining, while IL-27, IL-27 receptor subunit alpha (IL-27RA), FSIP1, and PI3K-Akt pathway proteins were measured through immunohistochemistry and WB. In addition, FSIP1 overexpression vectors and interfering constructs were utilized to examine the regulatory role of FSIP1 in the presence of IL-27.

RESULTS: Expression levels of IL-27 and IL-27RA were significantly elevated in OSCC. Treatment with IL-27 enhanced proliferation and migration, suppressed apoptosis, upregulated mesenchymal markers [Neural cadherin (N-cadherin), Vimentin], and downregulated the epithelial marker E-cadherin. Sequencing analysis identified FSIP1 as a key differentially expressed gene enriched in the PI3K-Akt pathway. IL-27 upregulated FSIP1 expression and elevated phosphorylation of PI3K and Akt (p-PI3K/PI3K, p-Akt/Akt). In the murine model, oral carcinogenesis was characterized by epithelial dysplasia, squamous epithelial thickening, and inflammatory cell infiltration. IL-27 treatment intensified these histopathological features and further upregulated protein expression. Overexpression of FSIP1 produced effects comparable to IL-27 treatment by enhancing malignant phenotypes and activating related pathways, while FSIP1 interference mitigated IL-27-induced cellular and molecular changes.

CONCLUSION: IL-27 promotes OSCC progression by upregulating FSIP1, leading to PI3K-Akt pathway activation, enhanced proliferation and migration, and reduced apoptosis. FSIP1 represents a central mediator of the oncogenic activity of IL-27 and may serve as a potential therapeutic target in OSCC.