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

Abstract

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.

Downregulated CDK10 promotes cancer progression and radioresistance in lung cancer through activating the JNK/c-Jun signaling pathway

“…Ectopic expression of CDK10 inhibited cell proliferation and migration in gastric cancer cells, and vice versa ( 26 ). Our study showed that CDK10 knockdown significantly increased cell growth and migration in lung cancer cells, which was consistent with a recent study ( 8 ). DNA double strand breaks (DSBs) can lead to cancer cell death after ionizing radiation, and γ-H2AX foci is a biomarker for DSBs ( 27 ), while radiosensitivity cell lines showed slower rates of γ-H2AX foci depletion ( 28 ).…”

“…CDK10 inhibited lung cancer cell growth and metastasis by inhibition of the ETS2/c-Raf/p-MEK/p-ERK signaling loop ( 8 ). The evidence was well established that the JNK/c-Jun signaling pathway was associated with cell proliferation, migration, invasion, and radioresistance in various cancers ( 20 , 21 , 29 , 30 ).…”

“…CDK10 is a Cdc2-related kinase serine/threonine kinase that is associated with cell growth, proliferation, and drug sensitivity ( 6 , 7 ). Initial studies have shown that CDK10 plays a tumor suppressor role in various tumors, such as glioma, lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma ( 8 - 11 ). Low CDK10 expression was related to poor clinical prognosis in gastric cancer and breast cancer ( 12 , 13 ).…”