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EPB41 suppresses the Wnt/β-catenin signaling in non-small cell lung cancer by sponging ALDOC
Cancer Letters ( IF 9.7 ) Pub Date : 2020-11-24 , DOI: 10.1016/j.canlet.2020.11.024
Jupeng Yuan , Huaixin Xing , Yankang Li , Yemei Song , Nasha Zhang , Mengyu Xie , Jiandong Liu , Yeyang Xu , Yue Shen , Bowen Wang , Li Zhang , Ming Yang

Despite advancements in therapeutic options, the overall prognosis for non-small-cell lung cancer (NSCLC) remains poor. Further exploration of the etiology and targets for novel treatments is crucial for managing NSCLC. In this study, we revealed the significant potential of EPB41 for inhibiting NSCLC proliferation, invasion and metastasis in vitro and in vivo. Consistent with its tumor suppressor role in NSCLC, the expression of EPB41 in NSCLC specimens evidently decreased compared to that in normal tissues, and low EPB41 expression was associated with poor prognoses for NSCLC patients. We further demonstrated the importance of EPB41 protein as a novel inhibitor of Wnt signaling, which regulates β-Catenin stability, and elucidated the crucial role of the EPB41/ALDOC/GSK3β/β-Catenin axis in NSCLC. Suppression of EPB41 expression in cancer cells elevated the levels of free ALDOC protein released from the EPB41-ALDOC complex, leading to disassembly of the β-catenin destruction complex, reduced proteolytic degradation of β-catenin, elevated cytoplasmic accumulation and nuclear translocation of β-catenin, thereby activating the expression of multiple oncogenes and, thus, NSCLC pathogenesis. Our study highlights the potential of EPB41 as a future therapeutic target for lung cancer.



中文翻译:

EPB41通过与ALDOC混合来抑制非小细胞肺癌中的Wnt /β-catenin信号传导

尽管治疗选择有所进步,但非小细胞肺癌(NSCLC)的总体预后仍然很差。进一步探索新疗法的病因和目标对于控制NSCLC至关重要。在这项研究中,我们揭示了EPB41在体外体内抑制NSCLC增殖,侵袭和转移方面的巨大潜力。与其在NSCLC中的抑癌作用相一致,与正常组织相比,NSCLC标本中EPB41的表达明显降低,并且EPB41表达与NSCLC患者预后差有关。我们进一步证明了EPB41蛋白作为一种新型Wnt信号抑制剂的重要性,该抑制剂可调节β-Catenin的稳定性,并阐明了EPB41 / ALDOC /GSK3β/β-Catenin轴在NSCLC中的关键作用。癌细胞中EPB41表达的抑制提高了从EPB41-ALDOC复合物释放的游离ALDOC蛋白的水平,导致β-catenin破坏复合物的解体,β-catenin的蛋白水解降解降低,细胞质积聚和β-连环蛋白,从而激活多种癌基因的表达,从而激活NSCLC发病机理。我们的研究强调了EPB41作为肺癌未来治疗靶标的潜力。

更新日期:2020-11-25
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