结直肠癌（CRC）的发展涉及Kirsten rat sarcoma病毒同源癌基因（KRAS）信号的激活。然而，KRAS的转录后调控尚未完全表征。本研究发现结直肠肿瘤差异表达（CRNDE）/异质核糖核蛋白A2/B1（hnRNPA2B1）轴在CRC中明显升高，并与患者预后不良密切相关，同时在体外和体内显著促进了CRC细胞增殖和转移。此外，CRNDE通过抑制E3泛素连接酶TRIM21介导的K63泛素化依赖蛋白降解，维持了hnRNPA2B1蛋白的稳定性。CRNDE/hnRNPA2B1轴促进了KRAS mRNA的核外转运和翻译，特异性激活了MAPK信号通路，最终加速了CRC的恶性进展。我们的研究结果揭示了hnRNPA2B1蛋白表达稳定性的调控网络，并深入阐明了CRNDE/hnRNPA2B1轴介导的KRAS核质转运和翻译的分子机制，强调hnRNPA2B1作为CRC有前景的生物标志物和治疗靶点。通过阻止hnRNPA2B1与E3泛素连接酶TRIM21的结合，抑制了泛素依赖降解，CRNDE保护了CRC中hnRNPA2B1高蛋白表达的稳定性。在高水平的致癌分子CRNDE的支持下，hnRNPA2B1结合到KRAS mRNA上，并促进其核外转运进入核糖体翻译程序，随后激活MAPK信号通路，最终加速CRC的恶性进展。© 2023. 作者。

Development of colorectal cancer (CRC) involves activation of Kirsten rat sarcoma viral oncogene homolog (KRAS) signaling. However, the post-transcriptional regulation of KRAS has yet to be fully characterized. Here, we found that the colorectal neoplasia differentially expressed (CRNDE)/heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1) axis was notably elevated in CRC and was strongly associated with poor prognosis of patients, while also significantly promoting CRC cell proliferation and metastasis both in vitro and in vivo. Furthermore, CRNDE maintained the stability of hnRNPA2B1 protein by inhibiting E3 ubiquitin ligase TRIM21 mediated K63 ubiquitination-dependent protein degradation. CRNDE/hnRNPA2B1 axis facilitated the nuclear export and translation of KRAS mRNA, which specifically activated the MAPK signaling pathway, eventually accelerating the malignant progression of CRC. Our findings provided insight into the regulatory network for stable hnRNPA2B1 protein expression, and the molecular mechanisms by which the CRNDE/hnRNPA2B1 axis mediated KRAS nucleocytoplasmic transport and translation, deeply underscoring the bright future of hnRNPA2B1 as a promising biomarker and therapeutic target for CRC. By hindering hnRNPA2B1 from binding to the E3 ubiquitin ligase TRIM21, whose mediated ubiquitin-dependent degradation was thereby inhibited, CRNDE protected the stability of hnRNPA2B1's high protein expression in CRC. Supported by the high level of the oncogenic molecule CRNDE, hnRNPA2B1 bound to KRAS mRNA and promoted KRAS mRNA nucleus export to enter the ribosomal translation program, subsequently activating the MAPK signaling pathway and ultimately accelerating the malignant progression of CRC.© 2023. The Author(s).