FOXO3/TRIM22 axis abated the antitumor effect of gemcitabine in non-small cell lung cancer via autophagy induction

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for more than 80% of the total lung cancer and gemcitabine (GEM)-based chemotherapy is the first-line therapeutic approach for NSCLC treatment. Owing to acquired chemo-resistance, the prognosis of NSCLC patients receiving GEM treatment is still poor. METHODS: Dysregulation of mRNAs in GEM-resistant (GR) NSCLC cells comparing to parental cells were profiled by analyzing GSEA6914 datasets from GEO database. Additionally, qRT-PCR were performed on clinically collected patient serum samples and transplanted tumor tissues and GEM-resistant (GR)/sensitive (GS) cell lines. In order to explore the functional role of tripartite motif protein 22 (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 puncta and western blot detection of autophagy markers were used to evaluate autophagy. Bi-luciferase reporter assay was used to confirm the transcriptional regulatory relationship. Rescue experiments were carried out to confirm the FOXO3/TRIM22 regulatory axis in GEM susceptibility. RESULTS: TRIM22 was significantly upregulated in GR patient serum samples, transplanted tumor tissues and NSCLC cells which was negatively transcriptional regulated by FOXO3. TRIM22 overexpression attenuated the sensitivity of A549 to GEM and its depletion promoted the sensitivity of A549/GR to GEM. Additionally, TRIM22 promoted GEM-induced pro-survival autophagy to protected NSCLC cells from apoptosis. CONCLUSIONS: TRIM22 was significantly upregulated in GR 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. This study may provide a basis for screening target of liquid biopsy for predicting GEM sensitivity in NSCLC.