Elimination of head and neck cancer initiating cells through targeting glucose regulated protein78 signaling

Mol Cancer. 2010 Oct 27;9:283. doi: 10.1186/1476-4598-9-283.

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) is a highly lethal cancer that contains cellular and functional heterogeneity. Previously, we enriched a subpopulation of highly tumorigenic head and neck cancer initiating cells (HN-CICs) from HNSCC. However, the molecular mechanisms by which to govern the characteristics of HN-CICs remain unclear. GRP78, a stress-inducible endoplasmic reticulum chaperone, has been reported to play a crucial role in the maintenance of embryonic stem cells, but the role of GRP78 in CICs has not been elucidated.

Results: Initially, we recognized GRP78 as a putative candidate on mediating the stemness and tumorigenic properties of HN-CICs by differential systemic analyses. Subsequently, cells with GRP78 anchored at the plasma membrane (memGRP78+) exerted cancer stemness properties of self-renewal, differentiation and radioresistance. Of note, xenotransplantation assay indicated merely 100 memGRP78+ HNSCCs resulted in tumor growth. Moreover, knockdown of GRP78 significantly reduced the self-renewal ability, side population cells and expression of stemness genes, but inversely promoted cell differentiation and apoptosis in HN-CICs. Targeting GRP78 also lessened tumorigenicity of HN-CICs both in vitro and in vivo. Clinically, co-expression of GRP78 and Nanog predicted the worse survival prognosis of HNSCC patients by immunohistochemical analyses. Finally, depletion of GRP78 in HN-CICs induced the expression of Bax, Caspase 3, and PTEN.

Conclusions: In summary, memGRP78 should be a novel surface marker for isolation of HN-CICs, and targeting GRP78 signaling might be a potential therapeutic strategy for HNSCC through eliminating HN-CICs.

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 Line
  • Cell Movement / genetics
  • Cell Movement / physiology
  • Flow Cytometry
  • Gene Expression Profiling
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • Oligonucleotide Array Sequence Analysis
  • RNA Interference
  • Signal Transduction*

Substances

  • Heat-Shock Proteins
  • molecular chaperone GRP78