BACKGROUND Long non-coding RNAs (lncRNAs) exert various functions in human cancers. However, the biological functions of lncRNAs in non-small cell lung cancer (NSCLC) are unknown. In the present study we investigated the tumor-suppressive role of lncRNA on chromosome 8p12 (TSLNC8) in the pathogenesis and progression of NSCLC. MATERIAL AND METHODS qRT-PCR was carried out to evaluate the expression of TSLNC8 in lung cancer cell lines. The effects of TSLNC8 on A549 cells proliferation, migration, and invasion were analyzed using CCK-8 assay, wound healing assay, Transwell assay, and Western blot analysis. We used flow cytometry to assess cell apoptosis, and cell autophagy was assessed by Western blot analysis and immunofluorescence staining. Levels of proteins in the IL-6/STAT3/HIF-1alpha pathway were measured by Western blot analysis. RESULTS The results revealed that TSLNC8 was significantly downregulated in lung cancer cells compared to normal bronchial epithelial cells. Further experiments showed that overexpression of TSLNC8 in A549 cells significantly inhibited proliferation in a time-dependent manner and promoted cell apoptosis. We found that TSLNC8 overexpression suppressed cell migration and invasion, and upregulation of TSLNC8 regulated the protein levels of Beclin-1, p62, ATG14, and LC3-II and inhibited the IL-6/STAT3/HIF-1alpha signaling pathway. CONCLUSIONS lncRNA TSLNC8 remarkably inhibited the proliferation and migration and accelerated apoptosis of lung cancer cells by targeting the IL-6/STAT3/HIF-1alpha signaling pathway. TSLNC8 may be a potential therapeutic target for the diagnosis and treatment of NSCLC.