T‑box transcription factor 15 regulated by methyltransferase‑like 3‑mediated N6‑methyladenosine modification promotes immune escape and progression of gastric cancer by activating matrix metalloproteinase 14 transcription

The present study aimed to investigate the involvement of T‑box transcription factor 15 (TBX15) in the immune evasion by gastric cancer (GC) cells, as well as the molecular pathways that regulate TBX15 upstream and downstream. GC and paracancerous tissues were collected to verify the expression of TBX15, matrix metalloproteinase 14 (MMP14) and methyltransferase‑like 3 (METTL3) using reverse transcription‑quantitative PCR and western blotting. The co‑culture system of GC cell‑tumor‑associated macrophages (TAMs) and mouse forestomach carcinoma (MFC) cell‑CD8⁺ T cells was constructed. TBX15, MMP14 and METTL3 were highly expressed in GC tissues. Kaplan‑Meier analyses were performed, and high TBX15 expression predicted a poor prognosis for patients with GC. Silencing TBX15 promoted GC cell apoptosis and inhibited tumor development and the activity of proliferation, migration and invasion. TBX15 targeted the MMP14 promoter by using ChIP‑qPCR. Overexpression of MMP14 attenuated the reduction caused by TBX15 silencing. METTL3 targets TBX15 mRNA and regulates the m6A level of TBX15. TBX15 is associated with macrophage and CD8⁺ T cell infiltration. In the co‑culture system of GC‑TAM and MFC‑CD8⁺ T cells, TBX15 overexpression alleviated the decrease in M2 polarization and activation of CD8⁺ T cell antitumor activity caused by METTL3 silencing. However, MMP14 overexpression resulted in TBX15 silence‑induced decreases in M1 macrophage polarization and CD8⁺ T cell activity. These data suggested that TBX15, correlated with poor prognosis in patients with GC, promotes immune escape in GC cells. TBX15, regulated by m6A methylation, targeted the MMP14 promoter, thereby regulating MMP14 expression. The METTL3/TBX15/MMP14 signaling axis was involved in GC cell development, M2 macrophage polarization and CD8⁺ T cell antitumor activity activation. These findings provide a fundamental experimental rationale for TBX15 as a potential therapeutic target for GC.