circ_EPHB4协同YTHDF3通过N6-甲基腺苷依赖性稳定Wnt3促进胶质瘤进展

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Abstract：ObjectiveTo investigatetheoncogenicroleof circularRNAcirc_EPHB4in gliomaanditsmolecularmechanism. MethodsMicroarrayanalysiswasperformedtoidentifythediferentiallyexpressedcircRNAsingliomatissues.Theefectsof circ_EPHB4onlioacelligratioasioandeitelial-mesenchaltrasition（EMinitroandumorigenicii wereassessedusingscratchwoundhalingassayanswelinvasionassyandnudemouse modelsbearingsubutaneous tumors.RNAimmunoprecipitation （RIP），RNAstabilityassays，andgeneoverexpresionandsilencingtechniqueswere employedto validate the synergisticregulatory effectof circ_EPHB4and the N6-methyladenosine （ m∘A ）readerprotein YTHDF3 on Wnt3 expresion. Results Circ_EPHB4 was significantly overexpressed by2.3 folds （llog2FCl=1.2， P<0.01 ）in gliomatissuescomparedtotheadjacent tisses，andby2.5foldsingiomacellineU373comparedtonormalcels（ P <0.001）. Overexpressonofcic_EPHB4 significantlyenhanced migrationand invasionofglioma cels，and promotedthe expresionsof EMTmarkersN-cadherinandvimentin.Inthetumor-bearingmousemodels，thetumorvolumeincirc_EPHB4overexpression groupwas significantly greaterthan that in the control group，and the lung metastatic foci increasedby 4.2 folds. Overexpressionofcirc_EPHB4promotedoncogenesis byupregulating Wnt3expression，whileYTHDF3extendedthehalf-life of Wnt3 mRNA in an m6A -dependent manner. Simultaneous knockdown of circ_EPHB4 and YTHDF3 resulted in an obvious reduction of Wnt3 mRNA expressionby up to 47% compared to its level following knocking down either circ_EPHB4 or YTHDF3 alone. Conclusion Circ_EPHB4 and YTHDF3 promote glioma progresion by jointly targetingthe Wnt3 signaling pathway，whichmayprovideanewtherapeuticstrategyforgliomas.

Keywords：circ_EPHB4; m6A YTHDF3;Wnt3;glioma

胶质瘤是第6大常见肿瘤，大多数胶质瘤患者确诊时已处于晚期，治疗效果不佳，5年生存率不到 20%[1-3] 因此，迫切需要明确胶质瘤分子机制以改变上述困境。（剩余15343字）