TUBB3 (βIII-tubulin) drives gastric cancer progression and poor prognosis by regulating cell cycle and invadopodia formation

Background Gastric cancer is the fifth most common malignancy and third leading cause of cancer death in China, with advanced-stage five-year survival below 20%. βIII-tubulin (TUBB3) is overexpressed in cancers but its role in gastric cancer remains unclear. Methods TUBB3 expression was analyzed using TCGA data and clinical samples. Knockdown models assessed its effects on proliferation, migration, and invasion in vitro and in vivo. Results TUBB3 was significantly upregulated in gastric cancer tissues versus normal mucosa. High TUBB3 correlated with poorer disease-free and overall survival but not other clinicopathological features. Functionally, TUBB3 knockdown inhibited proliferation via G2/M arrest and reduced migration/invasion by disrupting invadopodia, without affecting apoptosis, EMT, or ECM degradation. In vivo, TUBB3 depletion suppressed tumor growth and metastasis. Mechanistically, TUBB3 promoted G2/M transition via p21/Cyclin B1 and enhanced invasiveness through Cortactin/JNK activation. Conclusion TUBB3 overexpression predicts poor prognosis in gastric cancer. It drives proliferation via cell cycle regulation and metastasis through invadopodia formation, suggesting its potential as a therapeutic target.