Abstract
S100A4 is a calcium-binding protein capable of promoting epithelial-mesenchymal transition. Previously, we have demonstrated that S100A4 is required to sustain the head and neck cancer-initiating cells (HN-CICs) subpopulation. In this study, to further investigate the molecular mechanism, we established the head and neck squamous cell carcinoma (HNSCC) cell lines stably expressing mutant S100A4 proteins with defective calcium-binding sites on either N-terminal (NM) or C-terminal (CM), or a deletion of the last 15 amino-acid residues (CD). We showed that the NM, CM and CD harboring sphere cells that were enriched with HN-CICs population exhibited impaired stemness and malignant properties in vitro, as well as reduced tumor growth ability in vivo. Mechanistically, we demonstrated that mutant S100A4 proteins decreased the promoter activity of Nanog, likely through inhibition of p53. Moreover, the biophysical analyses of purified recombinant mutant S100A4 proteins suggest that both NM and CM mutant S100A4 were very similar to the WT S100A4 with subtle difference on the secondary structure, and that the CD mutant protein displayed the unexpected monomeric form in the solution phase.Taken together, our results suggest that both the calcium-binding ability and the C-terminal region of S100A4 are important for HN-CICs to sustain its stemness property and malignancy, and that the mechanism could be mediated by repressing p53 and subsequently activating the Nanog expression.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is a devastating cancer often refractory to chemotherapy and/or radiotherapy [1, 2]
Our results suggest that both the calcium-binding ability and the C-terminal region of S100A4 are important for head and neck cancer-initiating cells (HN-cancer initiating cells (CICs)) to sustain its stemness property and malignancy, and that the mechanism could be mediated by repressing p53 and subsequently activating the Nanog expression
Our previous study demonstrated that S100A4 is required to sustain the stemness and self-renewal property of the head and neck cancer-initiating cells (HN-CICs) population both in vitro and in vivo [26]
Summary
Head and neck squamous cell carcinoma (HNSCC) is a devastating cancer often refractory to chemotherapy and/or radiotherapy [1, 2]. The resistance of HNSCC to chemotherapy and/or radiotherapy is at least partly attributable to the subpopulation of cancer initiating cells (CICs), which exhibit stemness property and are capable www.impactjournals.com/oncotarget of initiating carcinogenesis or promoting metastasis [3,4,5,6,7,8,9]. For this reason, targeting the CICs in HNSCC would be an appealing modality for the treatment of this type of cancer. We demonstrated that HN-CICs promote EMT and stemness properties by CD133/Src signaling [15]
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