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Cyclin K interacts with ?-catenin to induce Cyclin D1 expression and facilitates tumorigenesis and radioresistance in lung cancer.

ABSTRACT: 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 ?-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 ?-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.

SUBMITTER: Yao G

PROVIDER: S-EPMC7532664 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Cyclin K interacts with β-catenin to induce Cyclin D1 expression and facilitates tumorigenesis and radioresistance in lung cancer.

Yao Guojun G Tang Jing J Yang Xijie X Zhao Ye Y Zhou Rui R Meng Rui R Zhang Sheng S Dong Xiaorong X Zhang Tao T Yang Kunyu K Wu Gang G Xu Shuangbing S

Theranostics 20200911 24

<b>Rationale:</b> 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. <b>Methods:</b> 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 formati ...[more]

PMID: 33042275

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Project description:Although mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcomes amongst lung cancer patients suggesting the importance of other pathways. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well defined role in colon and skin cancer but its role in lung cancer remains unclear. We show that activation of Wnt/β-catenin in the bronchiolar epithelium of the adult lung does not promote tumor development by itself. However, activation of Wnt/β- catenin signaling leads to a dramatic increase in tumor formation both in overall tumor number and size compared to KrasG12D alone. We show that activation of Wnt/β- catenin signaling significantly alters the KrasG12D tumor phenotype resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This is associated with a decrease in E- cadherin expression at the cell surface which may increase metastasis in Wnt/β-catenin signaling positive tumors. Together, these data suggest that activation of Wnt/β-catenin signaling in combination with other oncogenic pathways in lung epithelium may lead to a more aggressive phenotype due to the imposition of an embryonic distal progenitor phenotype accompanied by decreased E-cadherin expression. We performed microarray analysis of control murine lung, CC10-cre:KrasG12D, and CC10-cre:Ctnnb1ex3flox:LSL-KrasG12D double mutant micro-dissected murine lung tumors to determine their transcriptional phenotype. Lungs of five-month-old mice were PBS inflated and all the tumors in each lobe were dissected. The total number of tumors obtained from three out of the 5 pulmonar lobes of each animal was called a sample the other two lobes were saved in case there were problems and the array needed to be repeated. Trizol was used to isolate RNA for microarray analysis. Samples & Genotypes: control murine lung n=2 animals, CC10-cre:KrasG12D n=2 animals, and CC10-cre:Ctnnb1ex3flox:LSL-KrasG12D n=2 animals.

Dataset Information

Cyclin K interacts with ?-catenin to induce Cyclin D1 expression and facilitates tumorigenesis and radioresistance in lung cancer.

Publications

Cyclin K interacts with β-catenin to induce Cyclin D1 expression and facilitates tumorigenesis and radioresistance in lung cancer.

Similar Datasets

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