IFIT3 accelerates the progression of head and neck squamous cell carcinoma by targeting PD-L1 to activate PI3K/AKT signaling pathway

Background: Emerging evidence has shown interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) may be predicted to be a candidate oncogene and involved in the onset and progression of Cancer, but IFIT3's potential role in Cancer, particularly in head and neck squamous cell carcinoma (HNSC), is not well recognized. This study aims to reveal the role of IFIT3 in HNSC and the underlying molecular mechanism.

Methods: Bioinformatics analysis, immunohistochemical staining, RT-PCR, and Western blotting analysis were used to detect IFIT3 expression in HNSC. CCK-8 assays, colony formation assays, wound-healing assays, transwell assays, and sphere formation were used to explore proliferative, migratory, and invasive activities and Cancer stemness of HNSC cells after IFIT3 knockdown and over-expressed. The alterations of EMT markers and PI3K/Akt pathway were detected by Western blotting. Animal studies were performed to analyze the effect of IFIT3 on tumor growth and metastasis of HNSC in vivo.

Results: In this study, we observed that IFIT3 was highly expressed in HNSC, and its higher expression contributed to poorer survival of patients with clinical stage IV or grade 3. Function assay indicated that IFIT3 promoted malignant behaviors in vitro, as well as tumor growth and lung metastasis in vivo. Meanwhile, PD-L1 knockdown or over-expressed reversed Cancer cell stemness, migration, invasion, and PI3K/Akt signaling pathway which were regulated by IFIT3.

Conclusions: Our results reveal that IFIT3 promotes EMT and Cancer stemness by targeting PD-L1 to activate PI3K/Akt signaling pathway in HNSC, and targeting IFIT3 may be a novel strategy for the treatment of patients with HNSC.

CSCs; EMT; IFIT3; PD-L1; PI3K/AKT pathway.