Hypoxia-induced lncHILAR promotes renal cancer metastasis via ceRNA for the miR-613/206/ 1-1-3p/Jagged-1/Notch/CXCR4 signaling pathway

Mol Ther. 2021 Oct 6;29(10):2979-2994. doi: 10.1016/j.ymthe.2021.05.020. Epub 2021 May 29.


Hypoxia has been identified as a common contributor to tumor progression, including invasion and metastasis. However, the underlying mechanisms of enhanced invasion and metastasis under hypoxia remain unclear. A hypoxic microenvironment promotes invasion and metastasis of renal cell carcinoma (RCC) by upregulating expression of LOC100506178, which we named hypoxia-induced long non-coding RNA (lncRNA) associated with RCC (lncHILAR). Knockdown of lncHILAR inhibited cell invasion and migration, whereas overexpression of lncHILAR, conversely, facilitated cell invasion and migration of RCC cells. Notably, hypoxic RCC cells secreted exosomes packaged with lncHILAR, which were taken up by normoxic RCC cells and then drove normoxic cell invasion. Mechanistically, lncHILAR elevated RCC invasion and metastasis by acting as a competing endogenous RNA (ceRNA) for miR-613/206/1-1-3p, which led to the upregulation of Jagged-1 and the C-X-C motif chemokine receptor 4 (CXCR4). Activation of the Jagged-1/Notch/CXCR4 axis induced RCC metastasis. lncHILAR promotes RCC cell invasion and metastasis via ceRNA for the miR-613/206/1-1-3p/Jagged-1/Notch/CXCR4 axis. The novel lncHILAR may thus serve as a potential biomarker and therapeutic target in RCC.

Keywords: RCC; exosomes; hypoxia; lncRNA; metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / pathology*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / pathology*
  • Mice
  • MicroRNAs / genetics*
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • RNA, Long Noncoding / genetics*
  • Receptors, CXCR4 / genetics*
  • Receptors, Notch / genetics*
  • Tumor Hypoxia


  • CXCR4 protein, human
  • MIRN1 microRNA, human
  • MIRN206 microRNA, human
  • MIRN613 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • Receptors, CXCR4
  • Receptors, Notch