The FOXO family of transcription factors: key molecular players in gastric cancer

Gastric cancer (GC) is the fifth most frequently diagnosed cancer worldwide and the third leading cause of cancer-related death with an oncological origin. Despite its decline in incidence and mortality in recent years, GC remains a global public problem that seriously threatens patients’ health and lives. The forkhead box O proteins (FOXOs) are a family of evolutionarily conserved transcription factors (TFs) with crucial roles in cell fate decisions. In mammals, the FOXO family consists of four members FOXO1, 3a, 4, and 6. FOXOs play crucial roles in a variety of biological processes, such as development, metabolism, and stem cell maintenance, by regulating the expression of their target genes in space and time. An accumulating amount of evidence has shown that the dysregulation of FOXOs is involved in GC progression by affecting multiple cellular processes, including proliferation, apoptosis, invasion, metastasis, cell cycle progression, carcinogenesis, and resistance to chemotherapeutic drugs. In this review, we systematically summarize the recent findings on the regulatory mechanisms of FOXO family expression and activity and elucidate its roles in GC progression. Moreover, we also highlight the clinical implications of FOXOs in GC treatment.