Abstract 653: Clinical value and oncogenic role of METTL3 expression in gastric cancer patients

Abstract

Abstract Background: Gastric cancer (GC) is one of the most common cancers and leading cause of cancer-related deaths worldwide, primarily because of rapid disease progression to advanced stages and highly malignant potential. Methyltransferase-like 3 (METTL3) is a crucial component of the m6A methyltransferase complex, and plays pivotal roles in tumour progression. This study investigated the prognostic significance of METTL3 expression in gastric cancer (GC). Methods: We assessed expression levels of METTL3 by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) tissue specimens from one hundred fifty-eight GC patients. Propensity score matching (PSM) analysis was performed to clarify its prognostic potential. The METTL3 gene expression was also investigated in fresh frozen specimens from another independent cohort of fifty-seven GC patients to establish its clinical relevance. Knockdown of METTL3 by siRNA transfection was performed to evaluate its function in vitro. Results: METTL3 expression was significantly higher in cancerous tissues vs. corresponding normal mucosa (P<0.0001), and high METTL3 staining group was significantly associated with males (P=0.029), an advanced T stage (P=0.0002), the presence of venous invasion (P<0.0001), lymphatic vessel invasion (P=0.011), lymph node metastasis (P=0.004), distant metastasis (P=0.0004), and advanced TNM stage classification (P=0.0001) in the FFPE cohort of GC patients. Survival curve analysis showed that patients with increased expression of METTL3 showed poorer prognosis in terms of both overall survival (OS: P<0.0001, log-rank test) and disease-free survival (DFS: P=0.0005, log-rank test) compared to those with low expression. Multivariate analysis revealed that increased expression of METTL3 was an independent prognostic factor for overall survival (OS: hazard ratio (HR), 3.24; 95% confidence interval (CI), 1.57-6.68; p=0.001) and disease-free survival (DFS: HR, 2.4; 95% CI, 1.12-5.16; p=0.025) in the FFPE cohort of GC patients. PSM analysis revealed that elevated METTL3 expression was significantly associated with poor survival outcomes (OS: P=0.05; DFS: P=0.038; log-rank test), which was subsequently validated in another cohort of fresh frozen specimens (OS: p=0.007; DFS: p=0.029; log-rank test). The knockdown of METTL3 inhibited proliferation, invasion, migration, and anoikis resistance in GC cells. Conclusion: METTL3 expression may be used as a clinically feasible prognostic marker and could serve as a potential therapeutic target in GC patients. Citation Format: Yoshinaga Okugawa, Yuji Toiyama, Chengzeng Yin, Ma Ruiya, Akul Goel, Takashi Ichikawa, Hiroki Imaoka, Takahito Kitajima, Tadanobu Shimura, Mikio Kawamura, Hiromi Yasuda, Hiroyuki Fujikawa, Takeshi Yokoe, Ikuyo Mochiki, Masaki Ohi, Kaname Nakatani. Clinical value and oncogenic role of METTL3 expression in gastric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 653.