AGAP2‐AS1 promotes the assembly of m6A methyltransferases and activation of the IL6/STAT3 pathway by binding with WTAP in the carcinogenesis of gastric cancer

Abstract

AbstractOwing to the lack of biomarkers for early diagnosis, gastric cancer (GC) is often associated with a poor prognosis. Thus, there is an urgent need to identify early molecular targets in GC. Dysregulated long noncoding RNAs (lncRNAs) have been evaluated by integrated bioinformatics analysis; and we investigate their specific role and potential mechanism via N6‐methyladenosine (m6A) methylation modification in the carcinogenesis and progression of GC. In this study, we report upregulation of lncRNA AGAP2‐AS1, activated by a gain of H3K4Me3, in GC tissues and cells. AGAP2‐AS1 was linked to adverse prognosis in patients with GC. Functionally, AGAP2‐AS1 knockdown inhibited cell proliferation and migration of GC cells. Mechanistically, AGAP2‐AS1 bound WT1‐associated protein (WTAP) to promote the formation of the WTAP/methyltransferase‐like 3 (METTL3)/METTL14 m6A methyltransferase complex. AGAP2‐AS1 stabilized signal transducer and activator of transcription 3 (STAT3) mRNA in an m6A‐dependent manner and, thus, activated the interleukin 6 (IL6)/STAT3 pathway. Importantly, activation of the AGAP2‐AS1/WTAP/STAT3 pathways promoted cell proliferation and migration in GC. Collectively, the present findings revealed a novel regulatory relationship between lncRNA and m6A modification. Furthermore, targeting the AGAP2‐AS1/WTAP/STAT3 axis may be a promising strategy for the inhibition of inflammation‐mediated carcinogenesis and progression in GC.