Cyclin K interacts with β-catenin to induce Cyclin D1 expression and facilitates tumorigenesis and radioresistance in lung cancer.
Cyclin K interacts with β-catenin to induce Cyclin D1 expression and facilitates tumorigenesis and radioresistance in lung cancer.
复制标题
Cyclin K 与 β-catenin 相互作用诱导 Cyclin D1 表达并促进肺癌的肿瘤发生和放射抗性
作者：
Yao G;Tang J;Yang X;Zhao Y;Zhou R;Meng R;Zhang S;Dong X;Zhang T;Yang K;Wu G;Xu S
理由：放射抗性仍然是肺癌局部复发和远处转移的主要原因。然而，潜在的分子机制仍不清楚。本研究旨在探讨Cyclin K在肺癌放射抵抗中的作用及调控机制。方法：采用免疫组化法检测人肺癌组织及癌旁正常肺组织中Cyclin K的表达水平。细胞生长和增殖、中性彗星和病灶形成测定、G2/M 检查点和异种移植小鼠模型用于功能分析。通过RNA测序和定量实时PCR检查基因表达。通过免疫沉淀和 GST Pull-down 测定评估蛋白质-蛋白质相互作用。结果：我们报告 Cyclin K 经常过度表达，并与肺癌患者的不良预后相关。从功能上讲，我们证明 Cyclin K 耗尽会导致肺癌增殖减少、G2/M 检查点缺陷和放射敏感性增强。从机制上讲，我们揭示了 Cyclin K 与 β-catenin 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，我们证明 Cyclin D1 是介导 Cyclin K 在肺癌中生物学功能的主要效应器。结论：这些研究结果表明，Cyclin K 正向调节 β-catenin/Cyclin D1 轴，促进肺癌的肿瘤发生和放射抗性，表明 Cyclin K 可能是肺癌放疗的一种新型有吸引力的生物标志物。
Rationale: 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. Methods: 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. Results: 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. Conclusions: 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.