Inhibition of the AKT1/mTOR pathway through SIRT6 over expression downregulated the expression of programmed death-ligand 1 and prolonged overall survival in lung adenocarcinoma.

BACKGROUND

Programmed death-ligand 1 (PD-L1) is a common biomarker of immune checkpoint inhibitors (ICIs). The purpose of our study was to investigate the relationship between Sirtuin 6 (SIRT6) and PD-L1 expressions in lung adenocarcinoma.

METHODS

Recombinant plasmids containing green fluorescent protein (GFP)/no SIRT6 (h-NULL) and GFP/SIRT6 (h-SIRT6) were constructed and transfected into A549 cells by lentivirus as vector. The experiment was divided into control, h-NULL and h-SIRT6 groups. We detected apoptosis and the cell cycle by flow cytometry and observed migration and proliferation by wound-healing assays and methyl thiazolyl tetrazolium. The expressions of SIRT6, PD-L1, serine/threonine protein kinase-1 (AKT1), mammalian target of rapamycin (mTOR), B-cell lymphoma-2 (BCL-2) associated X protein (BAX), and BCL-2 were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. We retrospectively analyzed the relationship between SIRT6 expression and survival in lung adenocarcinoma treated by ICIs.

RESULTS

The expression of BAX, apoptosis rate, and proportion of G0G1 and G2M phases in the h-SIRT6 group were higher than in the control and h-NULL groups (P<0.05). The expressions of PD-L1, BCL-2, AKT1, and mTOR migration and proliferation rates and proportion of S phase in the h-SIRT6 group were lower than in the control and h-NULL groups (P<0.05). Survival in lung adenocarcinoma with high SIRT6 expression was better than with low SIRT6 expression.

CONCLUSIONS

SIRT6 over expression, through the inhibition of the AKT1/mTOR pathway, down-regulated PD-L1 expression, influenced biological behaviors, and prolonged survival of lung adenocarcinoma. SIRT6 expression may be a potential gene biomarker for immunotherapy in lung adenocarcinoma.