TRIM3 Suppresses Tumor Progression in Non-small-Cell Lung Cancer by Promoting PD-L1 Ubiquitination and Degradation.

[OBJECTIVES] Our objective was to investigate TRIM3 expression and its role in the immune microenvironment of non-small-cell lung cancer (NSCLC).

[MATERIALS AND METHODS] TRIM3 levels in NSCLC tissues and cells were detected by reverse transcriptase quantitative polymerase chain reaction. Cell viability and proliferation of lung cancer cells were evaluated by CCK-8 and EdU methods under the interference of TRIM3 expression. Meanwhile, CD8+ T cells were co-cultured with lung cancer cells, and the cytotoxicity against lung cancer cells was determined with a lactate dehydrogenase cytotoxicity detection kit. The role of TRIM3 on regulating tumor growth in vivo was also investigated in subcutaneous tumor xenograft models. The protein interaction between TRIM3 and programmed cell death-ligand 1 (PD-L1) was also studied according to immunoprecipitation followed by Western blotting assay.

[RESULTS] The messenger RNA levels of TRIM3 were significantly lower in lung cancers than in adjacent normal lung tissues according to the GEPIA analysis. The messenger RNA and protein levels of TRIM3 were all minimally expressed in collected NSCLC tissues and lung cancer cells. Cell viability of both A549 and H1299 cells with high expression of TRIM3 was significantly inhibited according to the results of the CCK-8 assay and EdU methods. TRIM3 over-expression promotes CD8+ T-cell cytotoxicity against lung cancer cells and inhibits tumor growth. Overexpression of TRIM3 can upregulate the ubiquitination level of PD-L1 and reduce the stability of PD-L1.

[CONCLUSIONS] This study reveals that TRIM3 functions as a tumor suppressor that can impede the tumorigenesis of NSCLC by degrading PD-L1, suggesting a novel therapeutic strategy against NSCLC.