Research
Elimination of head and neck cancer initiating cells through targeting glucose regulated protein78 signaling
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* Corresponding authors: Jeng-Fan Lo jflo@ym.edu.tw - Cheng-Chia Yu ccyu@csmu.edu.tw
- † Equal contributors
1 Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan
2 Department of Dentistry, National Yang-Ming University, Taipei, Taiwan
3 Department of Pathology, China Medical University and Hospital, Taichung, Taiwan
4 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
5 Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan
6 Graduate Institute of Chinese Medical Science and Institute of Medical Science, China Medical University, Taichung, Taiwan
7 Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
8 Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan
9 Institute of Oral Biology and Biomaterial Science, Chung Shan Medical University, Taichung, Taiwan
10 Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
Molecular Cancer 2010, 9:283 doi:10.1186/1476-4598-9-283
Published: 27 October 2010Abstract
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.