METTL3/m6A/IFIT2 regulates proliferation, invasion and immunity in esophageal squamous cell carcinoma

Abstract

Epigenetic regulation plays a critical role in the development, progression, and treatment of tumors. The most common chemical modification of mRNA, called m6A, is essential for controlling mRNA stability, splicing, and translation. Methyltransferase-like 3 (METTL3) is an important m6A methyltransferase. The mechanism of action of METTL3 in esophageal squamous cell carcinoma (ESCC) remains unclear. In this investigation, we sought to clarify the function and clinical importance of METTL3 in ESCC and investigate its underlying mechanisms. We discovered that METTL3 has a significant proliferative effect in ESCC cells by using lentiviral construction of stable cell lines overexpressing METTL3 (METTL3-OE) and knocking down METTL3 (sh-METTL3). To create a xenograft tumor model, we inoculated KYSE510 cells subcutaneously into BALB/c nude mice and discovered that sh-METTL3 inhibited the tumorigenicity of esophageal cancer KYSE510 cells in the nude mouse tumor model. MeRIP-seq and RNA-seq analysis revealed IFIT2 to be a METTL3 target gene. The findings revealed that METTL3 regulates IFIT2 and thus influences malignant biological behaviors such as proliferation, migration, and invasion of ESCC, as well as the immune microenvironment of tumors.

M6A reduction relieves FUS-associated ALS granules

“…1A). Furthermore, we evaluated the m 6 A reduction on mRNAs upon METTL3 decrease through the colorimetric EpiQuik assay and verified that the reduction was comparable with previously published works 14–16 (20%, Fig. S1e).…”

Tissue-specific atlas of trans-models for gene regulation elucidates complex regulation patterns

“…This regulation pattern is supported by previous publications, demonstrating that STAT1–STAT2–IRF9 form complexes, known as IFN-stimulated gene (ISG) factor 3 complexes [ 73 , 74 ]. Furthermore, high expression of STAT1, STAT2, and IRF9 in breast cells significantly increase the expression of IFIT3 after IFNβ treatment [ 75 ], are all highly expressed in cells such as esophageal squamous cell carcinoma [ 76 , 77 ] and that STAT2 could form a complex with IRF9 and bind to the IFN-stimulated gene regulatory element (ISRE) sequence on the IFIT3 promoter to promote IFIT3 transcription [ 78 ]. In another publication regarding patients with Chronic Hepatitis B Virus, STAT2 was essential for the production of IFIT3 but not STAT1 [ 79 ].…”

An integrated analysis of the anticarcinogenic role of forkhead box protein 1 in oesophageal squamous cell carcinoma

“…Specific lncRNAs, proteins, and related pathways have been confirmed to be involved in the development of oesophageal squamous cell carcinoma and the regulation of tumour immune infiltration. [42][43][44][45] Luo et al 46 also pointed out metabolic alteration mediated by hypoxia and TP53 mutation is related to regulation of tumour immune microenvironment across cancer types. Tumour immune infiltrating cells are related to the development of digestive system tumours.…”

“…Therefore, exploring factors regulating tumour immune infiltration levels is of importance. Specific lncRNAs, proteins, and related pathways have been confirmed to be involved in the development of oesophageal squamous cell carcinoma and the regulation of tumour immune infiltration 42–45 . Luo et al 46 .…”