Oral squamous cell carcinoma (OSCC) is a type of head and neck cancer (HNC) with a high recurrence rate, which has been reported to be associated with the presence of cancer stem cells (CSCs). Tribbles pseudokinase 3 (TRIB3) is involved in intracellular signaling and the aim of the present study was to investigate the role of TRIB3 in the maintenance of CSCs. Analysis of The Cancer Genome Atlas database samples demonstrated a positive correlation between TRIB3 expression levels and shorter overall survival rates in patients with HNC. Knockdown of TRIB3 in the SAS and HSC-3 OSCC cell lines reduced cell proliferation through the induction of cell cycle arrest, but not of apoptosis. The population of OSCC-CSCs, defined by a high level of intracellular aldehyde dehydrogenase activity and the ability to form tumorspheres, was also reduced in TRIB3-silenced OSCC cells. The tumorigenicity of tumorspheres derived from the SAS OSCC cell line was reduced following TRIB3 knockdown. These results suggested the potential involvement of TRIB3 in the self-renewal capability of the OSCC CSCs. Mechanistically, TRIB3 was shown to positively regulate SOX2 expression via maintaining both the protein expression level and the SOX2 promoter-binding capability of E2F transcription factor 1 (E2F1). Additionally, TRIB3 also increased the expression level of EGFR through preventing its lysosomal degradation. The significant associations between TRIB3 and E2F1, SOX2 or EGFR expression were also confirmed using a HNC tissue array. Taken together, the findings of the present study may suggest that TRIB3 is an oncogenic protein that supports the stemness of OSCC and that targeting TRIB3 may be a potential strategy for OSCC therapy in the future.

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