PDK1激活WNT4/β-连环蛋白/FOXO1信号通路可促进宫颈癌转移和上皮-间质转化过程。

Activation of the WNT4/ β-catenin/FOXO1 pathway by PDK1 promotes cervical cancer metastasis and EMT process.

作者信息

Chen Shidong, Zhang Cuixia, Huang Honglang, Wang Yuhuan, Lian Mingjian, Hong Guolin

机构信息

Department of Laboratory Medicine, Xiamen Key Laboratory of Genetic Testing, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, 55 Zhenhai Road, Siming District, Xiamen, 361003, Fujian, China.

Department of Pathology, Xiamen Pathology Quality Control Center, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.

出版信息

J Mol Histol. 2025 Jan 9;56(1):68. doi: 10.1007/s10735-024-10342-x.

DOI:10.1007/s10735-024-10342-x

PMID:39779500

Abstract

OBJECTIVE

This study aimed to elucidate the role of pyruvate dehydrogenase kinase-1 (PDK1) in cervical cancer (CC) by investigating its impact on cell proliferation, migration, and epithelial-mesenchymal transition (EMT) under hypoxic conditions.

METHODS

PDK1-silenced CC cell lines were established using lentiviral shRNA technology. Cell migration and invasion were assessed through scratch and Transwell assays, respectively. Cellular activity and apoptosis-related protein expression levels were evaluated using MTT assays and western blotting. Transcriptome sequencing elucidates the regulatory pathways impacted by PDK1 silencing, and rescue experiments confirmed the underlying mechanisms. Xenograft models with nude mice were used to validate the effects of PDK1 silencing on CC progression.

RESULTS

PDK1 silencing reduced migration, invasion, and cellular activity under hypoxic conditions while promoting apoptosis. Transcriptomic analysis revealed that PDK1 suppression downregulated the WNT4/β-catenin/FOXO1 pathway, decreasing EMT-related protein expression. Mechanistically, PDK1 enhanced β-catenin stability by inhibiting its phosphorylation through AKT-mediated GSK3β inactivation, promoting EMT and anti-apoptotic gene transcription.

CONCLUSIONS

Targeting PDK1 may provide novel therapeutic strategies specifically for CC by modulating the WNT4/β-catenin/FOXO1 pathway and associated EMT and apoptotic processes.

摘要

目的

本研究旨在通过研究丙酮酸脱氢酶激酶-1（PDK1）在缺氧条件下对细胞增殖、迁移和上皮-间质转化（EMT）的影响，阐明其在宫颈癌（CC）中的作用。

方法

使用慢病毒shRNA技术建立PDK1沉默的CC细胞系。分别通过划痕试验和Transwell试验评估细胞迁移和侵袭能力。使用MTT试验和蛋白质印迹法评估细胞活性和凋亡相关蛋白表达水平。转录组测序阐明了受PDK1沉默影响的调控途径，挽救实验证实了潜在机制。使用裸鼠异种移植模型验证PDK1沉默对CC进展的影响。