Shandong Provincial Key Laboratory of Radiation Oncology, Cancer Research Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
Department of Anesthesiology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong Province, China.
Cancer Lett. 2021 Feb 28;499:255-264. doi: 10.1016/j.canlet.2020.11.024. Epub 2020 Nov 24.
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 the 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.
尽管治疗选择有所进步，但非小细胞肺癌 (NSCLC) 的总体预后仍然不佳。进一步探索病因和新型治疗靶点对于 NSCLC 的治疗至关重要。在这项研究中，我们揭示了 EPB41 在体外和体内抑制 NSCLC 增殖、侵袭和转移的重要潜力。与 EPB41 在 NSCLC 中的肿瘤抑制作用一致，与正常组织相比，NSCLC 标本中 EPB41 的表达明显降低，而 EPB41 表达水平低与 NSCLC 患者预后不良相关。我们进一步证明了 EPB41 蛋白作为 Wnt 信号的新型抑制剂的重要性，Wnt 信号调节 β-连环蛋白的稳定性，并阐明了 EPB41/ALDOC/GSK3β/β-连环蛋白轴在 NSCLC 中的关键作用。癌细胞中 EPB41 表达的抑制会增加从 EPB41-ALDOC 复合物中释放的游离 ALDOC 蛋白的水平，导致 β-连环蛋白破坏复合物解体，β-连环蛋白的蛋白水解降解减少，β-连环蛋白在细胞质中的积累和核转位增加，从而激活多个癌基因的表达，进而促进 NSCLC 的发病机制。我们的研究强调了 EPB41 作为未来肺癌治疗靶点的潜力。
