LncRNA HOTAIR regulates HIF-1α/AXL signaling through inhibition of miR-217 in renal cell carcinoma

Cell Death Dis. 2017 May 11;8(5):e2772. doi: 10.1038/cddis.2017.181.

Abstract

Long non-coding RNA HOTAIR was regarded as an oncogene in multiple cancers. Previous studies have shown that HOTAIR is involved in the proliferation and tumorigenesis of renal carcinoma cells, while microRNA (miR)-217 functions as a tumor suppressor in renal cell carcinoma (Rcc). However, the underlying molecular mechanism of HOTAIR in Rcc, especially in association with miR-217, has not been studied. In this study, we first demonstrated that HOTAIR expression was upregulated, which was correlated with tumor progression, and miR-217 downregulated in Rcc tissues and cells. Importantly, HOTAIR expression was negatively correlated with miR-217 expression in Rcc tissues. Gain- and loss-of-function of HOTAIR revealed that HOTAIR functioned as a ceRNA for miR-217 to facilitate HIF-1α expression and then upregulated AXL level promoting Rcc proliferation, migration, and EMT process, and inhibiting apoptosis. Furthermore, HOTAIR knockdown suppressed tumor growth and reduced the expression of proliferation antigen ki-67, HIF-1α, and AXL, but upregulated the expression of miR-217 in vivo. Finally, with AXL inhibitor BGB324, we confirmed that HOTAIR promoted Rcc activity through AXL signaling both in vitro and in vivo. In conclusion, these results suggest that HOTAIR promotes Rcc tumorigenesis via miR-217/HIF-1α/AXL signaling, which may provide a new target for the diagnosis and therapy of Rcc disease.

MeSH terms

  • Axl Receptor Tyrosine Kinase
  • Benzocycloheptenes / pharmacology
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Male
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction*
  • Triazoles / pharmacology

Substances

  • Benzocycloheptenes
  • HIF1A protein, human
  • HOTAIR long untranslated RNA, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • MIRN217 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins
  • RNA, Long Noncoding
  • RNA, Neoplasm
  • Triazoles
  • bemcentinib
  • Receptor Protein-Tyrosine Kinases
  • Axl Receptor Tyrosine Kinase
  • AXL protein, human