ADAMTS12 promotes oxaliplatin chemoresistance and angiogenesis in gastric cancer through VEGF upregulation

Abstract

BackgroundWhile ADAMTS12 (A disintegrin and metalloproteinase with thrombospondin motifs 12) has been established as an important regulator of gastrointestinal tumor development and angiogenic activity, the precise mechanistic functions of ADAMTS12 have yet to be fully clarified in gastric cancer (GC). Accordingly, this study was developed to explore the molecular functions of ADAMTS12 in GC and to examine its utility as a biomarker associated with chemoresistance and prognostic outcomes in this cancer type. MethodsThe ability of ADAMTS12 to modulate the proliferative, migratory, invasive, chemoresistant, and tube formation activity of tumor cells was assessed in vivo and in vitro through gain- and loss-of-function approaches. Correlations between ADAMTS12, CD31, and VEGF expression levels in GC patient tumor tissue samples from individuals that did and did not undergo neoadjuvant chemotherapy (NAC) treatment were analyzed via immunohistochemical staining. ResultsThese analyses revealed the ability of ADAMTS12 to promote in vivo and in vitro cellular proliferative and angiogenic activity, promoting the activation of ERK and the consequent upregulation of VEGF, thereby inducing angiogenesis and decreasing GC cell oxaliplatin sensitivity. A positive correlation between ADAMTS12 levels and both the expression of VEGF as well as the density of microvessels was observed in GC patient tumor tissues. Moreover, those GC patients exhibiting higher intratumoral ADAMTS12 expression exhibited worse responses to NAC treatment and worse overall survival outcomes. ConclusionsThese findings suggest that ADAMTS12 can modulate signaling via the MAPK/VEGF axis in GC cells to enhance tumor cell resistance to oxaliplatin treatment under hypoxic and normoxic conditions. Elevated ADAMTS12 levels can additionally predict vascular abnormalities, worse survival outcomes, and chemoresistance in patients with GC.