METTL3 dual regulation of the stability of LINC00662 and VEGFA RNAs promotes colorectal cancer angiogenesis

Abstract

Purpose The angiogenesis is among the primary factors that affect tumor recurrence and distant organ metastasis in colorectal cancer (CRC). N 6-methyladenosine (m6A) modification is one of the most common chemical modifications in eukaryotic mRNA, especially at the post-transcriptional level. Methyltransferase-like 3 (METTL3) promoting angiogenesis in a variety of tumors has been reported. However, the mechanism of how METTL3 dual-regulates the stability of long non-coding RNAs (lncRNAs) and vascular-related factor RNAs to affect angiogenesis in CRC is unclear. Methods 64 paired CRC and adjacent normal tissues were collected. In vitro, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), actinomycin assay, methylated RNA immunoprecipitation (MeRIP) experiment,3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) and colony formation assay were performed. The functions were also studied in zebrafish model animals in vivo. Results We found that the vascular endothelial growth factor A(VEGFA), METTL3 and LINC00662 RNAs were highly expressed in CRC, and that METTL3 was significantly positively correlated with LINC00662 and VEGFA. The protein expression levels of CD31, CD34, VEGFA, m6A and METTL3 were all significantly increased in the CRC tissues. The angiogenesis experiments both in vivo and in vitro found that METTL3 and LINC00662 promoted angiogenesis in CRC. The actinomycin assay indicated that METTL3 maintained the stability of LINC00662 and VEGFA RNAs. In addition, the MeRIP experiment confirmed that the LINC00662 and VEGFA RNAs had METTL3-enriched sites. Conclusion These findings suggest that METTL3 and LINC00662 may both serve as diagnostic and prognostic predictive biomarkers for CRC and potential targets for anti-vascular therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s12672-022-00557-3.

Clostridium butyricum inhibits epithelial–mesenchymal transition of intestinal carcinogenesis through downregulating METTL3

“…RNA sequencing suggested SNHG10 upregulated expression in EMT‐derived exosomes 39,40 . Zhang et al found that METTL3 maintained VEGFA RNA stability to promote angiogenesis in CRC in vitro 41 . Methyltransferase‐like 3 upregulated PLAU mRNA through m6A modification, and regulated the MAPK/ERK pathway to promote angiogenesis and invasion in CRC 42 .…”

“… 39 , 40 Zhang et al found that METTL3 maintained VEGFA RNA stability to promote angiogenesis in CRC in vitro. 41 Methyltransferase‐like 3 upregulated PLAU mRNA through m6A modification, and regulated the MAPK/ERK pathway to promote angiogenesis and invasion in CRC. 42 Overexpression of METTL3 led to upregulation of proliferative CRC cells to promote further migration.…”

Overview of distinct N6-Methyladenosine profiles of messenger RNA in osteoarthritis

“…VEGFA is an essential member of vascular endothelial growth factor family and a crucial regulator of vasculogenesis and angiogenesis, with multiple signaling pathways and factors involved in the regulation of its expression. M6A modification facilitated the stability of VEGFA by preventing its mRNA degradation in colorectal cancer ( Zhang G. et al, 2022 ; Liu X. et al, 2022 ). Moreover, in bone mesenchymal stem cells, m6A modification participated in regulating the alternative splicing of VEGFA ( Tian et al, 2019 ).…”

Regulation of VEGF-A expression and VEGF-A-targeted therapy in malignant tumors

“…Mechanistically, METTL3 enhances m6A modification of VEGF-A which improves it interaction with IGF2BP2/3 and impedes the degradation of VEGF-A mRNA (Liu et al 2022a , b ; Yang et al 2020 ). The study of Zhang G et al also showed that METTL3 could enhance VEGF-A mRNA stability and protein level in colorectal cancer (Zhang et al 2022 ). In addition, m6A methylation of the internal ribosome entry site sequence A (IRES-A) at VEGF-A 5'UTR recruits the YTHDC2/eIF4GI complex to facilitate its’ cap-independent translation initiation (Zhang et al 2023 ).…”