CDK10 suppresses metastasis of lung adenocarcinoma through inhibition of the ETS2/c-Raf/p-MEK/p-ERK signaling loop.

Xiujuan Zhang, Yu Zhao, Ruzetuoheti Yiminniyaze, Ning Zhu, Yuanyuan Zhang, Gulinuer Wumaier, Jingwen Xia, Liang Dong, Daibing Zhou, Jing Wang, Chengwei Li, Youzhi Zhang, Shengqing Li

Molecular carcinogenesis 2024 Jan

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The repertoire of aberrant signaling underlying the pathogenesis of lung adenocarcinoma remains largely uncharacterized, which precludes an efficient therapy for these patients, especially when distant metastasis occurs. Cyclin-dependent kinase 10 (CDK10) has been reported to modulate the progression of malignant tumors; however, contradictory effects have been found among different types of malignant tumors. In the present study, we found that CDK10 was downregulated in lung adenocarcinoma compared with the paired adjacent normal lung tissue, and lower expression level of CDK10 was associated with more frequent N2 staged lymph node and distant metastasis, higher TNM stage, and shorter overall survival. Further study indicated that CDK10 inhibited the migration and invasion abilities with no impact on the proliferation of lung adenocarcinoma cells. Mechanistically, CDK10 could bind to and promote the degradation of ETS2, a transcription factor for C-RAF and MMP2/9, thereby inactivating the downstream c-Raf/p-MEK/p-ERK pathway that drives epithelial-mesenchymal transition and impairing the expression of matrix metalloproteinases involved in cell invasion. In addition, the p-MEK/p-ERK pathway conducts a positive feedback regulation on the expression of ETS2. Knockdown of CDK10 in human lung adenocarcinoma cells significantly promoted the formation of metastatic foci in lungs in a xenograft mouse model. In conclusion, CDK10 suppresses metastasis of lung adenocarcinoma by disrupting the ETS2/c-Raf/p-MEK/p-ERK/ETS2 signaling and MMP2/9, providing a new therapeutic target for the treatment of lung adenocarcinoma with metastasis. © 2023 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.

Citation

Xiujuan Zhang, Yu Zhao, Ruzetuoheti Yiminniyaze, Ning Zhu, Yuanyuan Zhang, Gulinuer Wumaier, Jingwen Xia, Liang Dong, Daibing Zhou, Jing Wang, Chengwei Li, Youzhi Zhang, Shengqing Li. CDK10 suppresses metastasis of lung adenocarcinoma through inhibition of the ETS2/c-Raf/p-MEK/p-ERK signaling loop. Molecular carcinogenesis. 2024 Jan;63(1):61-74