ADAMTS12 mediates vascular abnormality to enhance chemoresistance via the MAPK/VEGF signaling pathway in gastric cancer

Abstract

Abstract Purpose: A disintegrin and metalloproteinase with thrombospondin motifs 12 (ADAMTS12) is involved in the angiogenesis and tumorigenesis of gastrointestinal cancer. However, the exact molecular and biological mechanisms of ADAMTS12 in gastric cancer (GC) remain unclear. This study aims to explore the exact underlying mechanisms of ADAMTS12 and provide a biomarker for prognosis and chemotherapy in GC. Methods: Gain- and loss-of-function assays were used to reveal the effect of ADAMTS12 on cell proliferation, migration, invasion, tube formation and chemoresistance in vitro and in vivo. IHC was used to analyze the expression and the correlation between ADAMTS12, VEGF and CD31 in gastric cancer tissues with or without neoadjuvant chemotheraphy. Results: ADAMTS12 promotes cell proliferation, angiogenesis and chemoresistance in vitro and in vivo. ADAMTS12 upregulates VEGF expression through ERK activation, which in turn, promoting angiogenesis and reducing sensitivity to oxaliplatin in GC. In GC tissues, ADAMTS12 was positively correlated with VEGF and microvessel density (MVD). Furthermore, patients with high ADAMTS12 level had poor overall survival (OS) and poor response to neoadjuvant chemotherapy. Conclusion: ADAMTS12 enhances chemoresistance to oxaliplatin in normoxic and hypoxic microenvironments via the MAPK/VEGF signaling pathway in GC. High ADAMTS12 levels have prognostic significance for poor survival, and indicator of vascular abnormality and chemoresistance in GC.