Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Theranostics. 2020 Sep 11;10(24):11144-11158. doi: 10.7150/thno.42578. eCollection 2020.
Radioresistance remains the major cause of local relapse and distant metastasis in lung cancer. However, the underlying molecular mechanisms remain poorly defined. This study aimed to investigate the role and regulatory mechanism of Cyclin K in lung cancer radioresistance. Expression levels of Cyclin K were measured by immunohistochemistry in human lung cancer tissues and adjacent normal lung tissues. Cell growth and proliferation, neutral comet and foci formation assays, G2/M checkpoint and a xenograft mouse model were used for functional analyses. Gene expression was examined by RNA sequencing and quantitative real-time PCR. Protein-protein interaction was assessed by immunoprecipitation and GST pull-down assays. We report that Cyclin K is frequently overexpressed and correlates with poor prognosis in lung cancer patients. Functionally, we demonstrate that Cyclin K depletion results in reduced proliferation, defective G2/M checkpoint and enhanced radiosensitivity in lung cancer. Mechanistically, we reveal that Cyclin K interacts with and promotes the stabilization of β-catenin protein, thereby upregulating the expression of Cyclin D1. More importantly, we show that Cyclin D1 is the major effector that mediates the biological functions of Cyclin K in lung cancer. These findings suggest that Cyclin K positively modulates the β-catenin/Cyclin D1 axis to promote tumorigenesis and radioresistance in lung cancer, indicating that Cyclin K may represent a novel attractive biomarker for lung cancer radiotherapy.
放射抗拒仍是肺癌局部复发和远处转移的主要原因。然而，其潜在的分子机制仍未明了。本研究旨在探讨细胞周期蛋白 K 在肺癌放射抗拒中的作用及其调控机制。采用免疫组织化学法检测人肺癌组织及癌旁正常肺组织中细胞周期蛋白 K 的表达水平。通过细胞生长和增殖、中性彗星和焦点形成试验、G2/M 检查点和异种移植小鼠模型进行功能分析。采用 RNA 测序和实时定量 PCR 检测基因表达。通过免疫沉淀和 GST 下拉实验评估蛋白-蛋白相互作用。我们报告称，Cyclin K 在肺癌患者中经常过表达，并与预后不良相关。功能上，我们证明 Cyclin K 耗竭可导致增殖减少、G2/M 检查点缺陷和肺癌放射敏感性增强。在机制上，我们揭示了 Cyclin K 与 β-连环蛋白相互作用并促进其稳定，从而上调 Cyclin D1 的表达。更重要的是，我们表明 Cyclin D1 是介导 Cyclin K 在肺癌中发挥生物学功能的主要效应物。这些发现表明，Cyclin K 通过正向调节 β-连环蛋白/Cyclin D1 轴促进肺癌的发生和放射抗拒，表明 Cyclin K 可能成为肺癌放疗的一个有吸引力的新标志物。
