m6A methylated EphA2 and VEGFA through IGF2BP2/3 regulation promotes vasculogenic mimicry in colorectal cancer via PI3K/AKT and ERK1/2 signaling

Liu, Xin; He, Hongbin; Zhang, Fengwei; Hu, Xin; Bi, Fanqi; Li, Kai; Yu, Haoran; Zhao, Yue; Teng, Xiangyu; Li, Jiaqi; Wang, Lihong; Zhang, Yan; Wu, Qiong

doi:10.1038/s41419-022-04950-2

Cited by 98 publications

(53 citation statements)

References 50 publications

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“…Emerging evidence shows that m6A modification is associated with malignant phenotypes of tumors such as cell proliferation, differentiation, invasion and metastasis and functions as an oncogene in the development and progression of cancers ( 21 – 24 ). Similarly, the increased expression of METTL3 involved in regulating cell excessive proliferation, multidrug resistance, and distant metastasis in GC ( 25 – 27 ). Recent studies have shown that increased expression of METTL3 was associated with tumor cell glycolysis metabolism and sensitivity to glycolytic stress in hepatocellular carcinoma ( 28 ), and N(6)-methyladenosine regulates the glycolysis of cancer cells through PDK4 ( 14 ).…”

Section: Discussionmentioning

confidence: 99%

Integrative proteomics and m6A microarray analyses of the signatures induced by METTL3 reveals prognostically significant in gastric cancer by affecting cellular metabolism

et al. 2022

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METTL3-mediated RNA N6-methyladenosine (m6A) is the most prevalent modification that participates in tumor initiation and progression via governing the expression of their target genes in cancers. However, its role in tumor cell metabolism remains poorly characterized. In this study, m6A microarray and quantitative proteomics were employed to explore the potential effect and mechanism of METTL3 on the metabolism in GC cells. Our results showed that METTL3 induced significant alterations in the protein and m6A modification profile in GC cells. Gene Ontology (GO) enrichment indicated that down-regulated proteins were significantly enriched in intracellular mitochondrial oxidative phosphorylation (OXPHOS). Moreover, the protein-protein Interaction (PPI) network analysis found that these differentially expressed proteins were significantly associated with OXPHOS. A prognostic model was subsequently constructed based on the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, and the high-risk group exhibited a worse prognosis in GC patients. Meanwhile, Gene Set Enrichment Analysis (GSEA) demonstrated significant enrichment in the energy metabolism signaling pathway. Then, combined with the results of the m6A microarray analysis, the intersection molecules of DEPs and differential methylation genes (DMGs) were significantly correlated with the molecules of OXPHOS. Besides, there were significant differences in prognosis and GSEA enrichment between the two clusters of GC patients classified according to the consensus clustering algorithm. Finally, highly expressed and highly methylated molecules regulated by METTL3 were analyzed and three (AVEN, DAZAP2, DNAJB1) genes were identified to be significantly associated with poor prognosis in GC patients. These results signified that METTL3-regulated DEPs in GC cells were significantly associated with OXPHOS. After combined with m6A microarray analysis, the results suggested that these proteins might be implicated in cell energy metabolism through m6A modifications thus influencing the prognosis of GC patients. Overall, our study revealed that METTL3 is involved in cell metabolism through an m6A-dependent mechanism in GC cells, and indicated a potential biomarker for prognostic prediction in GC.

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Section: Discussionmentioning

confidence: 99%

Integrative proteomics and m6A microarray analyses of the signatures induced by METTL3 reveals prognostically significant in gastric cancer by affecting cellular metabolism

et al. 2022

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“…In reality, this signaling activates certain genes in surrounding the normal host tissue that causes proteins, such as proangiogenic factors, to encourage the growth of new blood vessels of solid tumors [17]. Vascular endothelial growth factor (VEGF), a proangiogenic factor, is a key mediator for the proper tumor vessel development, in which it is upregulated by oncogene expression, growth factors, and hypoxia [18][19][20]. VEGF mediates vascular EC survival, permeability, proliferation, and migration by binding and activating autophosphorylation of the tyrosine kinase receptors (VEGFR-2) [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction

Wei

Hao

Zheng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Brevilin A (BA), a sesquiterpene lactone isolated from Centipeda minima herb, has been identified to exhibit potent anticancer activity. However, the potential pharmacological effect and mechanism of BA in regulating endothelial cell (EC) angiogenesis, a key event in tumor growth, is poorly understood. In this study, BA was shown to significantly prevent vascular endothelial growth factor (VEGF) induced EC angiogenic capacities in vitro, ex vivo, and in vivo. Subsequent functional assays revealed that BA dose dependently inhibited VEGF-stimulated survival, proliferation, migration, and triggered apoptosis activity in human umbilical vein endothelial cells (HUVECs), as well as suppressed the expression of antiapoptotic protein Bcl-2, increased the expression of proapoptotic protein caspase-3 and Bax, and suppressed PI3K/AKT pathway. Meanwhile, BA was also able to depolarize mitochondrial membranal permeability (MMP), accelerate mitochondrial superoxide accumulation, induce intracellular reactive oxygen species (ROS) production, and decreased intracellular glutathione (GSH) in HUVECs. Furthermore, both mitochondria-specific superoxide scavenger Mito-TEMPOL and broad-spectrum antioxidant N-acetyl-cysteine (NAC) dramatically abolished BA-induced mitochondrial dysfunction and mitochondrial ROS production, causing the reversion of PI3K/AKT pathway and repression of apoptosis, eventually correcting the impaired endothelial behavior in survival, growth, migration, and angiogenesis. Collectively, our data for the first time identified a new mechanism for antiangiogenic effect of BA in vascular EC, one that is based on the regulation of mitochondrial-dependent ROS overproduction.

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“…As previous studies [33][34][35] , IGF2BP3 has been recognized as an m6A reader that regulates m6A-modi ed genes, which led us to hypothesize that STRIP2 regulates IGF2BP3-dependent gene in an m6Adenpendent manner. To test this hypothesis, we rst identi ed the potential m6A-modi ed site of TMBIM6 based on RMVar database (https://rmvar.renlab.org/) and the results showed that the 3'-UTR of TMBIM6 has an m6A site (Fig.…”

Section: Resultsmentioning

confidence: 82%

STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent

Zhang

Chen

et al. 2022

Preprint

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Background: Striatin interacting protein 2 (STRIP2) is a core component of the striatin-interacting phosphatase and kinase (STRIPAK) complexes, which is involved in tumor initiation and progression via the regulation of cell contractile and metastasis. However, the underlying molecular mechanisms of STRIP2 in non-small cell lung cancer (NSCLC) progression remain largely unknown. Methods: The expressions of STRIP2 and IGF2BP3 in human NSCLC specimens and NSCLC cell lines were detected using quantitative RT-PCR, western blotting, and immunohistochemistry (IHC) analyses. The roles and molecular mechanisms of STRIP2 in promoting NSCLC progression were investigated in vitro and in vivo. Results: Here, we found that STRIP2 expression was significantly elevated in NSCLC tissues and high STRIP2 expression was associated with a poor prognosis. Knockdown of STRIP2 suppressed tumor growth and metastasis in vitroand in vivo, while STRIP2 overexpression obtained the opposite effect. Mechanistically, P300/CBP-mediated H3K27 acetylation activation in the promoter of STRIP2 induced STRIP2 transcription, which interacted with insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and upregulated IGF2BP3 transcription. In addition, STRIP2-IGF2BP3 axis stimulated m6A modification of TMBIM6 mRNA and enhanced TMBIM6 mRNA stability. Consequently, TMBIM6 involved NSCLC cell proliferation, migration and invasion dependent on STRIP2 and IGF2BP3. In NSCLC patients, high co-expression of STRIP2, IGF2BP3 and TMBIM6 was associated with poor outcomes. Conclusions: Our findings indicate that STRIP2 interacts with IGF2BP3 to regulate TMBIM6 mRNA stability in an m6A-dependent manner and may represent a potential prognostic biomarker and therapeutic target for NSCLC.

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m6A methylated EphA2 and VEGFA through IGF2BP2/3 regulation promotes vasculogenic mimicry in colorectal cancer via PI3K/AKT and ERK1/2 signaling

Cited by 98 publications

References 50 publications

Integrative proteomics and m6A microarray analyses of the signatures induced by METTL3 reveals prognostically significant in gastric cancer by affecting cellular metabolism

Integrative proteomics and m6A microarray analyses of the signatures induced by METTL3 reveals prognostically significant in gastric cancer by affecting cellular metabolism

Brevilin A Inhibits VEGF-Induced Angiogenesis through ROS-Dependent Mitochondrial Dysfunction

STRIP2 motivates non-small cell lung cancer progression by modulating the TMBIM6 stability through IGF2BP3 dependent

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