MAGEA4 promotes gastric cancer progression by inducing chromosomal instability through the STAU1/c-Myc axis

This study aimed to investigate the clinical significance, biological function, and molecular mechanisms of MAGEA4 in the progression of gastric cancer (GC). Analysis of the TCGA database and 40 pairs of GC tissues and matched normal mucosa samples revealed that MAGEA4 expression was significantly upregulated in GC. Immunohistochemical analysis using two tissue microarrays containing 195 GC samples demonstrated that high MAGEA4 expression is significantly associated with advanced tumor stage, lymph node metastasis and unfavorable patient prognosis. Both in vitro and in vivo experiments confirmed that MAGEA4 significantly promoted the proliferation and metastasis of GC cells. Investigations of the underlying mechanisms revealed that MAGEA4 promotes GC progression by inducing chromosomal instability (CIN). This was evidenced by increased γH2AX (a sensitive DNA damage marker for double-strand breaks), abnormal chromosome numbers, abnormal mitosis, and other CIN features. At the molecular level, MAGEA4 binds E2F1 to enhance STAU1 transcription, subsequently promotes c-Myc translation and drives CIN. Knockdown of STAU1 effectively reversed the CIN and malignant phenotypes induced by MAGEA4 overexpression in GC cells, whereas overexpression of c‑Myc restores these phenotypes resulted from MAGEA4 knockdown. In summary, this research demonstrated the crucial role of MAGEA4 in promoting GC progression by inducing CIN via the E2F1/STAU1/c-Myc axis. Consequently, MAGEA4 represents a highly promising novel therapeutic target for GC.