Wei Liping, Jiang Zhaoyan, Chen Shujuan, Xia Ning, Kong Jiejun, Chang Yan, Hou Zhibo
China State Institute of Pharmaceutical Industry, Shanghai, P.R. China.
Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, P.R. China.
Anticancer Res. 2024 Dec;44(12):5405-5423. doi: 10.21873/anticanres.17367.
BACKGROUND/AIM: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality, yet its underlying molecular mechanisms remain poorly understood. Previous research has identified the pseudogene KRT17P3 as a key player in NSCLC chemoresistance, but its functional role in tumor development has not been thoroughly investigated.
In this study, we utilized in vitro assays to evaluate the impact of KRT17P3 on NSCLC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Additionally, we conducted in vivo experiments to assess tumor metastasis. The mechanisms underlying the action of KRT17P3 were explored through bioinformatics analyses, as well as RNA immunoprecipitation (RIP), luciferase, and chromatin immunoprecipitation (ChIP) assays.
Our findings revealed that KRT17P3 significantly enhances NSCLC cell proliferation, migration, invasion, and EMT, while also promoting tumor metastasis. We discovered that KRT17P3 stabilizes the oncogenic protein c-Myc by competitively binding to miR-338-3p, which leads to upregulation of deubiquitinase USP7. This stabilization of c-Myc serves as a critical driver of NSCLC tumorigenesis, with KRT17P3 expression being upregulated through FOXA1-mediated activation of its promoter.
KRT17P3 plays a pivotal role in NSCLC progression by regulating the USP7/c-Myc axis via miR-338-3p, suggesting its potential as both a prognostic biomarker and a therapeutic target for NSCLC treatment.
背景/目的：非小细胞肺癌（NSCLC）是癌症相关死亡的主要原因，但其潜在的分子机制仍知之甚少。先前的研究已确定假基因KRT17P3是NSCLC化疗耐药的关键因素，但其在肿瘤发生发展中的功能作用尚未得到充分研究。
在本研究中，我们利用体外实验评估KRT17P3对NSCLC细胞增殖、迁移、侵袭和上皮-间质转化（EMT）的影响。此外，我们进行了体内实验以评估肿瘤转移情况。通过生物信息学分析以及RNA免疫沉淀（RIP）、荧光素酶和染色质免疫沉淀（ChIP）实验探究KRT17P3发挥作用的机制。
我们的研究结果表明，KRT17P3显著增强NSCLC细胞的增殖、迁移、侵袭和EMT，同时促进肿瘤转移。我们发现KRT17P3通过竞争性结合miR-338-3p来稳定致癌蛋白c-Myc，从而导致去泛素化酶USP7上调。c-Myc的这种稳定是NSCLC肿瘤发生的关键驱动因素，KRT17P3的表达通过FOXA1介导的其启动子激活而上调。
KRT17P3通过miR-338-3p调节USP7/c-Myc轴在NSCLC进展中起关键作用，提示其作为NSCLC治疗的预后生物标志物和治疗靶点的潜力。
