Grp78 as a therapeutic target for refractory head-neck cancer with CD24- CD44+ stemness phenotype

C. C. Chiu, L. Y. Lee, Y. C. Li, Y. J. Chen, Y. C. Lu, Y. L. Li, H. M. Wang, J. T. Chang, A. J. Cheng

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Abstract

Cancer stem cells are refractory to conventional therapy, which result to cancer metastasis and chemo-radioresistance. Grp78 is known to have important roles in cytoprotection and tumorigenesis in several cancers. We therefore examined whether Grp78 can serve as a therapeutic target for refractory stemness phenotype of head and neck cancer (HNC). Six HNC cell lines were used. Fluorescence-activated cell sorting (FACS) analysis was used to sort CD24 - CD44+ and Grp78+ cells. The small interfering RNA (siRNA) knockdown and cDNA transfection were applied to examine the effects of Grp78 on cellular function. Western blot and confocol microscopy were used to determine the effects of downstream protein expressions. Xenografted mouse tumors and immunohistochemistry were used to validate the results. We found that Grp78 regulated the conversion of CD24- CD44+ cells, a characteristic of HNC stem cells. The CD24- CD44+ Grp78+ cells showed superior chemo-radioresistance and invasion ability compared with CD24- CD44+, Grp78+ or the parental cells. Silencing Grp78 increased chemo-radiosensitivity, inhibited cell invasion, reverse epithelial-mesenchymal transition, suppressed cancer stemness, withdrew CD24- CD44+ cell conversion and induced differentiated phenotype. Study in xenografted mice further showed that CD24- CD44- Grp78+ cells exhibited highest tumorigenesis, compared with CD24- CD44+ CD24+ CD44+ or the parental cells. Grp78 knockdown dramatically restrained tumor growth along with the inhibition of stem cell regulatory proteins Oct-4 and Slug. Grp78 may serve as a molecular target that can be further developed for eradication of refractory HNC with stemness phenotype.

Original languageEnglish
Pages (from-to)606-615
Number of pages10
JournalCancer Gene Therapy
Volume20
Issue number11
DOIs
Publication statusPublished - Nov 2013
Externally publishedYes

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Keywords

  • cancer stem cells
  • cell invasion
  • chemoresistance
  • Grp78
  • head and neck cancer
  • radioresistance

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Molecular Biology

Cite this

Chiu, C. C., Lee, L. Y., Li, Y. C., Chen, Y. J., Lu, Y. C., Li, Y. L., Wang, H. M., Chang, J. T., & Cheng, A. J. (2013). Grp78 as a therapeutic target for refractory head-neck cancer with CD24- CD44+ stemness phenotype. Cancer Gene Therapy, 20(11), 606-615. https://doi.org/10.1038/cgt.2013.64