Knockdown of m6A Reader IGF2BP3 Inhibited Hypoxia-Induced Cell Migration and Angiogenesis by Regulating Hypoxia Inducible Factor-1α in Stomach Cancer

Abstract

Hypoxia is a common feature of solid tumors including stomach cancer (SC) and is closely associated with cancer malignant progression. N6-methyladenosine (m6A), a common modification on RNA, is involved in the regulation of RNA fate and hypoxic responses in cancers. However, the interaction between m6A reader insulin-like growth factor-II mRNA-binding protein 3 (IGF2BP3) and SC hypoxic microenvironment is poorly defined. In the present study, expression levels of IGF2BP3 and hypoxia inducible factor-1α (HIF1A) were examined by bioinformatics analysis and RT-qPCR and western blot assays. Cell migratory ability was assessed through Transwell and wound healing assays. The angiogenic potential was evaluated by VEGF secretion, tube formation, and chick embryo chorioallantoic membrane (CAM) assays. The interaction between IGF2BP3 and HIF1A was explored using bioinformatics analysis and RIP and luciferase reporter assays. The results showed that IGF2BP3 and HIF1A were highly expressed in SC tissues and hypoxia-treated SC cells. IGF2BP3 knockdown inhibited hypoxia-induced cell migration and angiogenesis in SC. IGF2BP3 positively regulated HIF1A expression by directly binding to a specific m6A site in the coding region of HIF1A mRNA in SC cells. HIF1A overexpression abrogated the effects of IGF2BP3 knockdown on hypoxia-induced cell migration and angiogenesis in SC. In conclusion, IGF2BP3 knockdown inhibited hypoxia-induced cell migration and angiogenesis by down-regulating HIF1A in SC.

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

“…Regulation of the m 6 A reader YTHDF2 by hypoxia involves enhanced inflammation and angiogenesis and thus is critical for tumor invasion [ 195 ]. Overexpression of IGF2BP3 upregulates HIF-α in gastric cancer and promotes hypoxia-induced angiogenesis and tumor invasion [ 196 ]. In addition, tumor metabolism in hypoxic TME favors angiogenesis.…”

“…For instance, hypoxia in breast cancer induces HIF-1α expression and promotes the effect of PKM2 on glycolysis through upregulation of YTHDF1, triggering cancer cell growth and metastasis [ 206 ]. In fact, all known metastatic mechanisms involving CSCs [ 166 ], angiogenesis [ 196 ], EMT [ 207 ], chemoresistance [ 208 ] and autophagy [ 81 ] are associated with hypoxia and metabolism to varying degrees. However, the potential roles of m 6 A methylation in other metastatic processes, such as tumor cell entry and exit from dormancy, tumor-associated regulation of biological circadian rhythms, and signaling networks that promote metastatic colonization and evolution, remain to be established.…”

The role of Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as m6A readers in cancer

“…In colon cancer, high expression of IGF2BP3 is associated with poorer overall survival, and IGF2BP3 recognizes and binds to the CDS region of Cyclin D1 to regulate cycle, and IGF2BP3 also regulates angiogenesis through m 6 A modification of vascular endothelial growth factor (VEGF) 176 . In gastric cancer, IGF2BP3 directly binds to hypoxia inducible factor-1a (HIF1A) at a specific m 6 A site in the CDS region, and knockout of IGF2BP3 inhibits cell migration and angiogenesis induced by hypoxia 177 . In addition, IGF2BP3 can bind to the m 6 A-modified region of the ATP-binding cassette transporters subfamily B member 1 (ABCB1) and promotes its mRNA stabilization, thereby triggering chemoresistance of colorectal cancer cells 178 .…”

ALKBH5 Promotes Multiple Myeloma Tumorigenicity through inducing m6A-demethylation of SAV1 mRNA and Myeloma Stem Cell Phenotype

“… 40 However, in MM, the addition of bevacizumab to anti-MM therapies (bortezomib or thalidomide) did not result in a significant improvement in the outcome of patients, which were probably related to the complexity of the BM microenvironment by a myriad of proangiogenic cytokines and other active pro-angiogenic pathways. 41 Some latest reports displayed that m6A modifiers manipulated angiogenesis via modulating VEGF expression either directly targeting specific m6A sites of VEGF mRNA 42 - 44 or indirectly mediating by other downstream miRNAs and proteins. 45 , 46 In our study, the secretion of VEGF decreased after silencing ALKBH5 gene expression in MM cells, addressing the angiogenesis-promoting effect of ALKBH5.…”