Yang Mengdi, Lu Yudie, Zheng Jingrong, Zhao Xinran, Wu Guangping, Wang Enhua, Zhao Huanyu
Department of Pathology, The First Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China.
Translational Medicine Center, Huaihe Hospital of Henan University, Kaifeng, Henan, China.
Oncogene. 2025 Sep 19. doi: 10.1038/s41388-025-03580-0.
Prickle planar cell polarity protein 3 (PRICKLE3) is involved in tumor malignant progression. However, little information is available regarding its detailed mechanism in non-small cell lung cancer (NSCLC). The clinicopathological significance of PRICKLE3 in NSCLC specimens was assessed. PRICKLE3-overexpression and PRICKLE3-knockout NSCLC cells were generated in vivo and in vitro. The interaction among PRICKLE3, ubiquitin-specific peptidase 9, X-chromosome (USP9X) and dishevelled2 (DVL2) in NSCLC cells was identified. We found that PRICKLE3 overexpression was correlated with advanced TNM stage, lymphatic metastasis, and poor prognosis in NSCLC patients. PRICKLE3 knockdown inhibited the viability, colony formation, and invasiveness in A549 and H1299 cells, and its overexpression promoted the viability, colony formation, and invasiveness in HBE, H460, and LK2 cells. PRICKLE3 promoted NSCLC growth in vivo. PRICKLE3-DVL2 interaction enhanced the β-catenin phosphorylation at serine 675 for β-catenin nuclear translocation. Furthermore, PRICKLE3 interacted with USP9X to inhibit the DVL2 ubiquitination for the DVL2 stability and the activation of canonical WNT signaling. Overall, we demonstrate a novel signal transduction pathway where PRICKLE3 interacts with USP9X and DVL2 to enhance the DVL2 deubiquitination mediated by USP9X for stabilizing DVL2 expression and activate the canonical WNT signaling for promoting the NSCLC progression.
棘状平面细胞极性蛋白3（PRICKLE3）参与肿瘤的恶性进展。然而，关于其在非小细胞肺癌（NSCLC）中的详细机制，目前所知甚少。我们评估了PRICKLE3在NSCLC标本中的临床病理意义。在体内和体外构建了PRICKLE3过表达和PRICKLE3基因敲除的NSCLC细胞。确定了NSCLC细胞中PRICKLE3、泛素特异性肽酶9、X染色体（USP9X）和散乱蛋白2（DVL2）之间的相互作用。我们发现，PRICKLE3过表达与NSCLC患者的晚期TNM分期、淋巴转移及预后不良相关。敲低PRICKLE3可抑制A549和H1299细胞的活力、集落形成和侵袭能力，而过表达PRICKLE3则可促进HBE、H460和LK2细胞的活力、集落形成和侵袭能力。PRICKLE3在体内促进NSCLC生长。PRICKLE3与DVL2的相互作用增强了β-连环蛋白丝氨酸675位点的磷酸化，从而促进β-连环蛋白的核转位。此外，PRICKLE3与USP9X相互作用，抑制DVL2的泛素化，以维持DVL2的稳定性并激活经典WNT信号通路。总体而言，我们证明了一种新的信号转导途径，即PRICKLE3与USP9X和DVL2相互作用，增强由USP9X介导的DVL2去泛素化，以稳定DVL2表达并激活经典WNT信号通路，从而促进NSCLC进展。
