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

• Published in: Molecular cancer Vol. 9; no. 1; p. 283
• Main Authors: Wu, Meng-Ju, Jan, Chia-Ing, Tsay, Yeou-Guang, Yu, Yau-Hua, Huang, Chih-Yang, Lin, Shu-Chun, Liu, Chung-Ji, Chen, Yu-Syuan, Lo, Jeng-Fan, Yu, Cheng-Chia
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 27.10.2010; BioMed Central; BMC
• Subjects: Animals; Biology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Line; Cell Movement - genetics; Cell Movement - physiology; Cellular signal transduction; Flow Cytometry; Gene Expression Profiling; Genetic aspects; Head & neck cancer; Head and neck cancer; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Health aspects; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Humans; Immunohistochemistry; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular chaperones; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oligonucleotide Array Sequence Analysis; Physiological aspects; Protein folding; Risk factors; RNA Interference; Rodents; Science; Signal Transduction; Stem cells; Survival analysis; Taiwan
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-9-283

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. 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. 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.