Hypoxia inducible factor-1α promotes non-small cell lung cancer progression by activating leptin receptor transcription.

BackgroundHypoxia and leptin receptors (also called obesity receptors, OB-R) are evident markers of tumor progression and have been demonstrated to be essential oncogenes in a variety of cancers. However, the specific role of OB-R in lung cancer, especially non-small cell lung cancer (NSCLC) and its correlation with HIF1α remains unclear. Present study aims to explore the potential functions and mechanisms of OB-R in NSCLC.MethodsThe RNA levels of HIF1α and OB-R in NSCLC cells were detected by quantitative real-time PCR (qRT-PCR) and western blotting. The HIF-1α, OB-R, and Ki67 levels in tumor tissues were detected by immunohistochemistry. CCK8 assays for proliferation, transwell assays for migration were performed to determine the role of HIF-1α and OB-R , while subcutaneous tumors in nude mice were used for functional studies. Mechanically, chromatin immunoprecipitation and luciferase reporter gene analyses were executed to determine the relationship between HIF-1α and OB-R.ResultsqRT-PCR and western blotting revealed that HIF-1α and OB-R was highly expressed in NSCLC cells. Moreover, hypoxia up-regulated OB-R expression in NSCLC cells via HIF-1α. Hence, down-regulating HIF-1α significantly reduced the mRNA level of OB-R. In addition, HIF-1α silencing reduced cell proliferation and migration . Xenograft mouse models indicated that decrease of HIF-1α led to tumor growth by decreasing OB-R . Mechanically, we unveiled that HIF-1α bound to the promoter region (-831 to -824) and positively regulated OB-R expression by activating its transcription. Additionally, by immunohistochemical staining, we observed that high levels of HIF-1α and OB-R were positively associated with tumor size and lymph node metastasis.ConclusionIn conclusion, our present results demonstrated that HIF-1α positively regulates the expression of OB-R, which acts as an oncogene in NSCLC. HIF-1α and OB-R are potential therapeutic targets in NSCLC.