Background Data on the incidence, mortality, and other burden of oral cancer as well as their secular trends are necessary to provide policy‐makers with the information needed to allocate resources appropriately. The purpose of this study was to use the Global Burden of Disease (GBD) 2017 results to estimate the incidence, mortality, and disability‐adjusted life years (DALYs) for oral cancer from 1990 to 2017. Methods We collected detailed data on oral cancer from 1990 to 2017 from the GBD 2017. The global incidence, mortality, and DALYs attributable to oral cancer as well as the corresponding age‐standardized rates (ASRs) were calculated. The estimated annual percentage changes in the ASRs of incidence (ASRI) and mortality (ASRM) and age‐standardized DALYs of oral cancer were also calculated according to regions and countries to quantify the secular trends in these rates. Results We tracked the incidence, mortality, and DALYs of oral cancer in 195 countries/territories over 28 years. Globally, the incidence, mortality, and DALYs of oral cancer increased by about 1.0‐fold from 1990 to 2017. The ASRI of oral cancer showed a similar trend, increasing from 4.41 to 4.84 per 100,000 person‐years during the study period. The ASRM remained approximately stable at about 2.4 per 100,000 from 1990 to 2017, as did the age‐standardized DALYs, at about 64.0 per 100,000 person‐years. ASRI was highest in Pakistan (27.03/100,000, 95% CI = 22.13‐32.75/100,000), followed by Taiwan China, and lowest in Iraq (0.96/100,000, 95% CI = 0.86‐1.06/100,000). ASRM was highest in Pakistan (16.85/100,000, 95% CI = 13.92‐20.17/100,000) and lowest in Kuwait (0.51/100,000, 95% CI = 0.45‐0.58/100,000). Conclusions The ASRI of oral cancer has increased slightly worldwide, while the ASRM and age‐standardized DALY have remained stable. However, these characteristics vary between countries, suggesting that current prevention strategies should be reoriented, and much more targeted and specific strategies should be established in some countries to forestall the increase in oral cancer.

Autophagy modulation is a potential therapeutic strategy for tongue squamous cell carcinoma (TSCC). Melatonin possesses significant anticarcinogenic activity. However, whether melatonin induces autophagy and its roles in cell death in TSCC are unclear. Herein, we show that melatonin induced significant apoptosis in the TSCC cell line Cal27. Apart from the induction of apoptosis, we demonstrated that melatonin-induced autophagic flux in Cal27 cells as evidenced by the formation of GFP-LC3 puncta, and the upregulation of LC3-II and downregulation of SQSTM1/P62. Moreover, pharmacological or genetic blockage of autophagy enhanced melatonin-induced apoptosis, indicating a cytoprotective role of autophagy in melatonin-treated Cal27 cells. Mechanistically, melatonin induced TFE3 dephosphorylation, subsequently activated TFE3 nuclear translocation, and increased TFE3 reporter activity, which contributed to the expression of autophagy-related genes and lysosomal biogenesis. Luzindole, a melatonin membrane receptor blocker, or MT2-siRNA partially blocked the ability of melatonin to promote mTORC1/TFE3 signaling. Furthermore, we verified in a xenograft mouse model that melatonin with hydroxychloroquine or TFE3-siRNA exerted a synergistic antitumor effect by inhibiting autophagy. Importantly, TFE3 expression positively correlated with TSCC development and poor prognosis in patients. Collectively, we demonstrated that the melatonin-induced increase in TFE3-dependent autophagy is mediated through the melatonin membrane receptor in TSCC. These data also suggest that blocking melatonin membrane receptor-TFE3-dependent autophagy to enhance the activity of melatonin warrants further attention as a treatment strategy for TSCC.