The 5-year survival rate of head and neck squamous cell carcinoma (HNSCC), which accounts for 90% of all head and neck cancers, is approximately 50% (Economopoulou et al., 2019). Its morbidity and mortality rank seventh among all reported cancers (Ferlay et al., 2015). OSCC accounts for 90% of all HNSCCs (Singh et al., 2021) and is the maximum frequent type of head and neck malignancy worldwide. Therefore, OSCC is a primary long-term social health problem (Zhang et al., 2019). In spite of recent advances in surgery, adjuvant radiation, and chemotherapy, the 5-year survival rate of OSCC remains low at about 50-60% (Liu et al., 2022). This is mostly driven by the lack of effective treatment targets and the fact that the current combination of surgery and radiotherapy for OSCC is not ideal (Martinez et al., 2013). Therefore, finding new therapeutic targets for OSCC to reduce the rate of chemotherapy resistance and exploring new molecular mechanisms and effective therapeutic targets for the treatment of OSCC are very important to improve the overall survival rate of the patients, which is still the direction of future efforts.

FAM72 is a specific protein (Rahane et al., 2019a) of neural stem cells that not only participates in the signaling pathways of neurons in the brain (Benayoun et al., 2014, Nehar et al., 2009) but also has a major role in supporting the self-renewal of neural progenitor cells (Kutzner et al., 2015). FAM72 consists of four similar genes in the human genome (FAM72A-D) (Wahlgren et al., 2008, Wintermark et al., 2013, Zaidat et al., 2013), which are particularly engaged in the modulation of mitotic cell cycle genes and are instrumental in promoting centrosomal and mitotic spindle formation (Rahane et al., 2019a). FAM72 had lower expression levels in other tissues under physiological conditions; however, under some circumstances, it may contribute to post-mitotic neuronal death and the appearance of lung cancer (Yu et al., 2021), adrenal cortical tumors (Rahane et al., 2019b), multiple myeloma (Chatonnet et al., 2020), prostate cancer (Rajan et al., 2014), and glioblastoma multiform (Ho et al., 2021, Rahane et al., 2019a) in tissues other than the nerve tissue (Yu et al., 2021). A significant clinical correlation between FAM72 and the survival and prognosis were observed in a number of non-neurogenic cancers (Guo et al., 2008, Nehar et al., 2009, Wang et al., 2011). The expression of FAM72 is triggered by oncogene mutation (Rahane et al., 2019a), which participates in the division, proliferation, and differentiation of cancer cells (Ho et al., 2017, Yu et al., 2021). In addition, methylation levels have gained increasing attention in the field of cancer diagnosis, treatment, and prognosis. High levels of FAM72 have been reported to be correlated with low methylation, which affects the prognosis of various cancers. In conclusion, FAM72 is a potential cancer prognosis biomarker (Yu et al., 2021). Nevertheless, FAM72 has not been identified as a factor in the prognosis of OSCC, and its relationship with OSCC has not yet been reported.

The function of FAM72 in OSCC was analyzed in this study. We analyzed FAM72A-D level in OSCC and its clinical prognostic value using TCGA. Our team firstly analyzed the differences in FAM72 between tumors and normal tissues in OSCC patients. Single and multiple COX regression models (CRM) were applied to explore the associations between FAM72 and clinical pathology of OSCC. The nomogram was further developed for prognostic prediction, and its predictive performance was analyzed. To deeply investigate the biological mechanism of FAM72, our team performed GO and GSEA and comprehensively investigate the correlation between FAM72 and OSCC. At last, we demonstrated that FAM72B and FAM72C were expressed differently in cancer and paraneoplastic tissues in OSCC, HOK and Cal-33 by RT-qPCR, which laid a solid foundation for a follow-up study on the effects of FAM72B and FAM72C on OSCC and the underlying mechanisms. FAM72B and FAM72C are promising prognostic molecules and therapeutic targets in OSCC.