ANGPTL6-mediated Angiogenesis Promotes Alpha Fetoprotein-producing Gastric Cancer Progression

Alpha-fetoprotein (AFP)-producing gastric cancer (AFPGC) is regarded as a rare but highly malignant gastric adenocarcinoma subtype and its clinic pathological presentation mimics hepatocellular carcinoma. However, the underlying mechanism of this disease remains elusive. The level of ANGPTL6 in AFPGC cell lines is much higher than that of common types of gastric cancer cells. A high level of ANGPTL6 confers a poor prognosis and is correlated with the expression of CD34 (an endothelial cell marker). ANGPTL6 promotes endothelial cell migration and tube formation, Moreover, ANGPTL6 knockdown inhibits cancer cell apoptosis and invasiveness. Mechanistically, ANGPTL6 activates the ERK1/2 and AKT pathways. Treatment of ERK1/2 or AKT inhibitor can attenuated cell migration and tube formation. ANGPTL6 loss results in tumor growth in vivo. Our study revealed that ANGPTL6 is an important driver gene of angiogenesis in AFPGC development. These findings provide not only an effective biomarker for diagnosis but also an attractive therapeutic target for use in AFPGC patients.