ARNT2 is Downregulated and Serves As a Potential Tumor Suppressor Gene in Non-small Cell Lung Cancer

The present study aims to investigate the expression pattern of aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) protein and its clinical significance in human non-small cell lung cancer (NSCLC). We investigated the expression levels of ARNT2 in 104 NSCLC surgical specimens by immunohistochemistry and then analyzed its clinical significance. Additionally, the role of ARNT2 on the biological properties of the NSCLC line HCC827 was experimentally tested in vitro and in vivo to confirm the clinical observations. We found that the expression level of ARNT2 was significantly higher in normal lung tissues compared with NSCLC tissues (P < 0.01). Overall survival (OS) of patients with a high intratumoral ARNT2 level was significantly longer than survival of those with a low ARNT2 level (P = 0.004). In addition, intratumoral ARNT2 expression was an independent prognostic factors for OS (hazard ratio [HR] = 0.529; P = 0.001). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that the ARNT2 overexpression inhibited cell viability, while ARNT2 knockdown promoted cell growth in NSCLC cell lines HCC827 and A549. Annexin V/PI assay showed that ARNT2 overexpression increased cell apoptosis, while ARNT2 knockdown decreased cell apoptosis in HCC827 and A549 cells. Moreover, in vivo study showed that attenuated ARNT2 expression in HCC827 cells greatly promoted tumor growth, while overexpressed ARNT2 remarkably inhibited tumor growth in a HCC827 xenograft model. Taken together, our data demonstrate that ARNT2 might serve as a tumor suppressor in NSCLC progression.