HNRNPA2B1 and HNRNPR stabilize mRNA in neuroblastoma, but whether their regulatory effects depend on m6A modification and whether their function involves ASCL1 remain unknown. This study investigated the m6A-dependent binding of HNRNPA2B1 and HNRNPR to ASCL1 and subsequent regulation, as well as the expression, clinical significance, and function of HNRNPA2B1 and HNRNPR in neuroblastoma. We revealed that METTL14 mediated ASCL1 m6A modification to stabilize . HNRNPA2B1 and HNRNPR significantly enriched mRNA by binding to the 5′ and 3′ untranslated regions, respectively, and METTL14 knockdown reduced this enrichment. Mutations in m6A sites in the untranslated regions of mRNA considerably decreased probe capacity to engage HNRNPA2B1 and HNRNPR. HNRNPR interacts with IGF2BP1, and knocking down either impaired binding to mRNA. HNRNPA2B1 and HNRNPR knockdown suppressed neuroblastoma cell growth and invasion, while ASCL1 overexpression restored these effects. The high HNRNPA2B1 and HNRNPR expression in neuroblastoma correlated with ASCL1 expression. Thus, HNRNPA2B1 and HNRNPR bind and stabilize mRNA in an m6A-dependent manner to promote neuroblastoma progression. This study not only discovered a new mechanism underlying the high ASCL1 expression in neuroblastoma but also identified the HNRNPA2B1/HNRNPR/ASCL1 axis as a promising target for inhibiting neuroblastoma progression.

中文翻译：

---

HNRNPA2B1 和 HNRNPR 以 m6A 依赖性方式稳定 ASCL1，促进神经母细胞瘤进展

HNRNPA2B1和HNRNPR稳定神经母细胞瘤中的mRNA，但它们的调节作用是否依赖于m6A修饰以及它们的功能是否涉及ASCL1仍然未知。本研究探讨了 HNRNPA2B1 和 HNRNPR 与 ASCL1 的 m6A 依赖性结合及其后续调控，以及 HNRNPA2B1 和 HNRNPR 在神经母细胞瘤中的表达、临床意义和功能。我们发现 METTL14 介导 ASCL1 m6A 修饰以稳定。HNRNPA2B1 和 HNRNPR 分别通过与 5' 和 3' 非翻译区结合显着富集 mRNA，而 METTL14 敲低则减少了这种富集。mRNA 非翻译区 m6A 位点的突变显着降低了探针结合 HNRNPA2B1 和 HNRNPR 的能力。HNRNPR 与 IGF2BP1 相互作用，并消除任一受损的 mRNA 结合。HNRNPA2B1 和 HNRNPR 敲低抑制了神经母细胞瘤细胞的生长和侵袭，而 ASCL1 过表达则恢复了这些作用。神经母细胞瘤中 HNRNPA2B1 和 HNRNPR 的高表达与 ASCL1 表达相关。因此，HNRNPA2B1 和 HNRNPR 以 m6A 依赖性方式结合并稳定 mRNA，以促进神经母细胞瘤进展。这项研究不仅发现了神经母细胞瘤中 ASCL1 高表达的新机制，而且还确定了 HNRNPA2B1/HNRNPR/ASCL1 轴作为抑制神经母细胞瘤进展的有希望的靶点。