Lung cancer is the leading cause of cancer-related deaths worldwide and non-small cell lung cancer (NSCLC) accounts for over 80% of lung cancer cases. The RNA binding protein, QKI, belongs to the STAR family and plays tumor-suppressive functions in NSCLC. QKI-5 is a major isoform of QKIs and is predominantly expressed in NSCLC. However, the underlying mechanisms of QKI-5 in NSCLC progression remain unclear. We found that QKI-5 regulated microRNA (miRNA), miR-196b-5p, and its expression was significantly up-regulated in NSCLC tissues. Up-regulated miR-196b-5p promotes lung cancer cell migration, proliferation, and cell cycle through directly targeting the tumor suppressors, GATA6 and TSPAN12. Both GATA6 and TSPAN12 expressions were down-regulated in NSCLC patient tissue samples and were negatively correlated with miR-196b-5p expression. Mouse xenograft models demonstrated that miR-196b-5p functions as a potent onco-miRNA, whereas TSPAN12 functions as a tumor suppressor in NSCLC in vivo. QKI-5 bound to miR-196b-5p and influenced its stability, resulting in up-regulated miR-196b-5p expression in NSCLC. Further analysis showed that hypomethylation in the promoter region enhanced miR-196b-5p expression in NSCLC. Our findings indicate that QKI-5 may exhibit novel anticancer mechanisms by regulating miRNA in NSCLC, and targeting the QKI5∼miR-196b-5p∼GATA6/TSPAN12 pathway may enable effectively treating some NSCLCs.

BackgroundTriple-negative breast cancer (TNBC) is an aggressive subgroup of human breast cancer. Patients with TNBC have poor clinical outcome as they are non-responsive to current targeted therapies. There is an urgent need to identify new therapeutic targets and develop more effective treatment options for TNBC patients. Osthole, a natural product from C. monnieri, has been shown to inhibit certain cancer cells. However, the mechanisms of action as well as its effect on TNBC cells are not currently known.MethodsWe investigated the effect of osthole in cultured TNBC cells as well as in a xenograft model of TNBC growth. We also used a high-throughput proteomics platform to identify the direct binding protein of osthole.ResultsWe found that osthole inhibited the growth of a panel of TNBC cells and induced apoptosis in both cultured cells and TNBC xenografts. We used a high-throughput proteomics platform and identified signal transducer and activator of transcription 3 (STAT3) as a potential binding protein of osthole. We further show that osthole suppressed STAT3 in TNBC cells to inhibit growth and induce apoptosis. Overexpressing STAT3 in TNBC reduced the effectiveness of osthole treatment.ConclusionsThese results provide support for osthole as a potential new therapeutic agent for the management of TNBC. Moreover, our results indicate that STAT3 may be targeted for the development of novel anti-TNBC drugs.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0992-z) contains supplementary material, which is available to authorized users.

No abstract