WTAP-Mediated N6-Methyladenosine Modification Promotes Gastric Cancer Progression by Regulating MAP2K6 Expression.

Abstract

Wilms tumor 1 associated protein (WTAP) is a key RNA N6-methyladenosine (m⁶A) methylase, which is involved in gastric cancer (GC) development, but its pathogenic mechanism is not clear. This study aims to thoroughly explore the underlying molecular mechanism of WTAP-mediated m⁶A modification in GC pathogenesis. qRT-PCR and immunohistochemistry showed that significantly elevated WTAP expression in GC tissues and is related to advanced age, poorly differentiation, lymph node metastasis and high TNM stage. Overexpression and knockdown of WTAP could promote or inhibit the proliferation, migration and invasion of GC cells in vitro, furthermore, suppression of WTAP expression impeded the growth of xenograft tumors in vivo. Utilizing RNA sequencing, methylated RNA immunoprecipitation (MeRIP) sequencing and bioinformatics analysis, we identified MAP2K6 as direct downstream target of WTAP with m⁶A modification in GC. The interaction between WTAP and MAP2K6 was confirmed by MeRIP-qPCR, luciferase reporter assay, Co-IF and bioinformatics prediction. Immunofluorescence and rescue studies were performed to verify WTAP-mediated m⁶A modification promotes the proliferation, migration, and invasion of GC cells by positively regulating the target gene MAP2K6. This underscores the potential therapeutic significance of targeting the WTAP-MAP2K6 axis in combating GC occurrence and progression.