Abstract

TRIM22 Abated the Antitumor Effect of Gemcitabine in Non-small Cell Lung Cancer via Autophagy Induction

 Background:Non-small cell lung cancer(NSCLC) accountsformore than 80% ofthe total lung cancer and gemcitabine-based chemotherapy isthe first-line therapeutic approach for the NSCLC treatment. Owing to acquired chemo-resistance, the prognosis of NSCLC patients receiving gemcitabine (GEM) treatment is still poor. 
Methods and findings: the dysregulation of mRNAs in GEM-resistant NSCLC cells comparing to parental cells were profiled by analysing GSEA6914 datasets from GEO databases. Additionally, qRT-PCR was performed on transplanted tumor tissues of node mice and GEM-resistant/sensitive cell lines. In order to explore the functional role of TRIM22, gain and loss-of-function cell models were constructed in A549 and A549/GR respectively. MTT and Annexin V-FITC/propidium iodide (PI) staining assay were carried out to access the response to GEM of A549 and A549/ GR cells. Observation of RFP-LC3 punctate structures and western blot detection of autophagy markers were used to evaluate autophagy. Bi-luciferase reporter assay was used to confirm the transcriptional regulatory relationship. 
Discussion: TRIM22 was significantly upregulated in GEM-resistant NSCLC cells and transplanted tumor tissues which was negatively transcriptional regulated by FOXO3. TRIM22 overexpression could attenuate the sensitivity of A549 cells to GEM and its depletion could promote the sensitivity of A549/GR cells to GEM. Additionally, TRIM22 promotedGEM-induced pro-survival autophagy to protected NSCLC cells from apoptosis.
Conclusion: TRIM22 was significantly upregulated in GEM-resistant lung adenocarcinoma cell line A549 which is negatively transcriptional regulated by FOXO3. Due to the enhancement of pro-survival autophagy induced by TRIM22, the A549 cells became less sensitive to GEM.


Author(s):

Yang Wang, Heng-xing Liang, Chun-min Zhang, Min Zou, Bi-bo Zou, Wei Wei and Wen Hu



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