最近的研究表明，Hippo/Yes 相关蛋白 (YAP) 轴的失调与多种癌症类型（包括肺腺癌 (LUAD)）的肿瘤进展和治疗耐药相关。了解Hippo信号在LUAD中的调控具有重要意义。 TRIB3（一种假激酶）水平升高，已在某些肺部恶性肿瘤中观察到，并与不良预后相关。我们的研究旨在调查 TRIB3 水平升高是否通过其与 Hippo 信号通路的相互作用增强 LUAD 细胞的恶性特征和肿瘤进展。在这项研究中，我们报告了 TRIB3 表达升高与 LUAD 进展之间呈正相关。此外，TRIB3 能够增强 TEAD 荧光素酶功能并抑制 Hippo 通路活性。此外，TRIB3 增加 YAP 总蛋白水平并促进 YAP 核定位。机制实验表明，TRIB3 直接与大肿瘤抑制激酶 1 (LATS1) 相互作用，从而抑制 Hippo 信号传导。此外，METTL3介导的TRIB3 N6-甲基腺苷修饰的减少导致其在LUAD细胞中的表达水平大幅升高。总的来说，我们的研究揭示了一个新发现，即 TRIB3 通过与 LATS1 相互作用并抑制 Hippo 信号通路来增强 LUAD 细胞的生长和侵袭。 TRIB3 可能作为不良预后的潜在生物标志物和 YAP 驱动的肺癌新治疗的靶点。© 2024 Wiley periodicals LLC。

Recent studies have indicated that dysregulation of the Hippo/Yes-associated protein (YAP) axis is associated with tumor progression and therapy resistance in various cancer types, including lung adenocarcinoma (LUAD). Understanding the regulation of Hippo signaling in LUAD is of great significance. Elevated levels of TRIB3, a pseudo kinase, have been observed in certain lung malignancies and are associated with an unfavorable prognosis. Our research aims to investigate whether increased TRIB3 levels enhance the malignant characteristics of LUAD cells and tumor progression through its interaction with the Hippo signaling pathway. In this study, we reported a positive correlation between elevated expression of TRIB3 and LUAD progression. Additionally, TRIB3 has the ability to enhance TEAD luciferase function and suppress Hippo pathway activity. Moreover, TRIB3 increases total YAP protein levels and promotes YAP nuclear localization. Mechanistic experiments revealed that TRIB3 directly interacts with large tumor suppressor kinase 1 (LATS1), thereby suppressing Hippo signaling. Moreover, the decrease in METTL3-mediated N6-methyladenosine modification of TRIB3 results in a substantial elevation of its expression levels in LUAD cells. Collectively, our research unveils a novel discovery that TRIB3 enhances the growth and invasion of LUAD cells by interacting with LATS1 and inhibiting the Hippo signaling pathway. TRIB3 may serve as a potential biomarker for an unfavorable prognosis and a target for novel treatments in YAP-driven lung cancer.© 2024 Wiley Periodicals LLC.