Abstract 1737: METTL3-mediated m6A modification promotes tumor progression in upper tract urothelial carcinoma

Abstract Upper tract urothelial carcinoma (UTUC), comprising 5% of urothelial neoplasms, is a rare malignancy arising from the transitional epithelium of the renal pelvis and ureter. Its rarity and diverse histology pose diagnostic and therapeutic challenges, often lead to delayed diagnoses. The absence of targeted therapies, coupled with a limited understanding of molecular pathogenesis, underscores the ongoing research in urological oncology for effective UTUC management. N6-methyladenosine (m6A) is the predominant RNA methylation in mammalian cells, with its inscription primarily orchestrated by METTL3, a crucial methyltransferase. METTL3 has been implicated in various cancers, affecting critical processes like proliferation, migration, and tumor progression. However, the specific mechanisms and biological function of how METTL3/m6A regulates the progression of UTUC remain unclear. In our study, we found that m6A modification and METTL3 expression were elevated in aggressive UTUC, both are negatively correlated with unfavorable clinical outcomes and poor patient survival. By overexpressing METTL3 in less aggressive UTUC cell lines BFTC909 and KTCC28, the abilities of cell proliferation, migration, invasion, and colony formation increased. Notably, overexpression of METTL3 also increased tumor growth and metastasis in the in vivo orthotopic mouse model. In contrast, knockdown of METTL3 decreases tumor progression in a highly aggressive UTUC cell line KTCC28M. Furthermore, our comparative analysis of RNA-seq and m6A MeRIP-seq datasets unveiled the regulation of 1660 genes by METTL3. This diverse set includes genes associated with tumor growth and metastasis (such as MYC, JAK2, and STAT3), as well as RNA processing-related genes which their critical roles in modulating mRNA stability and splicing (such as GEMIN5 and PABPC1L). Together, we noticed METTL3/m6A is a crucial protagonist in the oncogenic landscape of UTUC, which suggested that it can be used as a target for novel therapeutic strategy for UTUC treatment. Citation Format: LI-JIE LIN, PEI-HUA PENG, KAI-WEN HSU. METTL3-mediated m6A modification promotes tumor progression in upper tract urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1737.