Receptor activator of NF-κB ligand induces cell adhesion and integrin α2 expression via NF-κB in head and neck cancers

Sci Rep. 2016 Mar 24:6:23545. doi: 10.1038/srep23545.


Cellular interactions with the extracellular matrix play critical roles in tumor progression. We previously reported that receptor activator of NF-κB ligand (RANKL) specifically facilitates head and neck squamous cell carcinoma (HNSCC) progression in vivo. Here, we report a novel role for RANKL in the regulation of cell adhesion. Among the major type I collagen receptors, integrin α2 was significantly upregulated in RANKL-expressing cells, and its knockdown suppressed cell adhesion. The mRNA abundance of integrin α2 positively correlated with that of RANKL in human HNSCC tissues. We also revealed that RANK-NF-κB signaling mediated integrin α2 expression in an autocrine/paracrine manner. Interestingly, the amount of active integrin β1 on the cell surface was increased in RANKL-expressing cells through the upregulation of integrin α2 and endocytosis. Moreover, the RANK-integrin α2 pathway contributed to RANKL-dependent enhanced survival in a collagen gel and inhibited apoptosis in a xenograft model, demonstrating an important role for RANKL-mediated cell adhesion in three-dimensional environments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Survival
  • Gene Expression Regulation, Neoplastic
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Humans
  • Integrin alpha2 / genetics*
  • Integrin alpha2 / metabolism
  • Mice
  • NF-kappa B / metabolism*
  • Neoplasm Transplantation
  • RANK Ligand / genetics*
  • RANK Ligand / metabolism*
  • Signal Transduction


  • Integrin alpha2
  • NF-kappa B
  • RANK Ligand
  • TNFSF11 protein, human