HNRNPA2B1-mediated m6A modification of lncRNA MEG3 facilitates tumorigenesis and metastasis of non-small cell lung cancer by regulating miR-21-5p/PTEN axis

Background: Increasing data imply that heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as a nuclear N6-methyladenosine (m 6 A) reader acts crucial roles in cancer progression. However, the role and underlying mechanism by which HNRNPA2B1-mediated m 6 A modification of lncRNA contributes to non-small cell lung cancer (NSCLC) remain undocumented. Methods The association of HNRNPA2B1 expression with the clinicopathological characteristics and prognosis in patients with NSCLC was determined by qRT-PCR, Western blot, immunohistochemistry and public datasets. The role of HNRNPA2B1 in NSCLC cells was assessed by the in vitro experiments and in vivo tumorigenesis and metastasis models. The m 6 A-lncRNA epi-transcriptomic microarray was employed to screen HNRNPA2B1-mediated m 6 A modification of lncRNAs, which were verified by methylated RNA immunoprecipitation (Me-RIP), RT-qPCR and rescue experiments in NSCLC cells. lncRNA MEG3-specific binding with miR-21-5p was validated by luciferase gene report and RIP assays. The effects of HNRNPA2B1 and (or) lncRNA MEG3 on miR-21-5p/PTEN/PI3K/AKT signaling were examined by RT-qPCR and Western blot analyses. Results We found that upregulation of HNRNPA2B1 was associated with distant metastasis and represented an independent prognostic factor for poor survival in patients with NSCLC. Knockdown of HNRNPA2B1 impaired cell proliferation and metastasis of NSCLC cells in vitro and in vivo , whereas ectopic expression of HNRNPA2B1 possessed the opposite effects. Mechanical investigations revealed that lncRNA MEG3 was identified as an m 6 A target of HNRNPA2B1 and inhibition of HNRNPA2B1 decreased the m 6 A level of lncRNA MEG3 but increased its expression levels. Furthermore, lncRNA MEG3 acted as a sponge of miR-21-5p, and knockdown of lncRNA MEG3 attenuated sh-HNRNPA2B1-caused inhibitory effects on cell colony formation and invasion. Elevated expression of miR-21-5p indicated poor survival in patients with NSCLC and inhibition of miR-21-5p counteracted si-MEG3-induced PTEN downregulation and PI3K/AKT signaling activation in NSCLC cells. Conclusions Our findings uncover that HNRNPA2B1-mediated m 6 A modification of lncRNA MEG3 promotes tumorigenesis and metastasis of NSCLC cells by regulating miR-21-5p/PTEN axis.