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

Cancer Biomark. 2025 Feb;42(2):18758592251330479. doi: 10.1177/18758592251330479. Epub 2025 Apr 3.

Abstract

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 in vitro, while subcutaneous tumors in nude mice were used for in vivo 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 in vitro. Xenograft mouse models indicated that decrease of HIF-1α led to tumor growth by decreasing OB-R in vivo. 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.

Keywords: Hypoxia inducible factor-1α; leptin receptor; non-small cell lung cancer; transcription.

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit* / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Receptors, Leptin* / genetics
  • Receptors, Leptin* / metabolism

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, Leptin
  • HIF1A protein, human
  • LEPR protein, human