Research Papers:

Attenuation of cancer-initiating cells stemness properties by abrogating S100A4 calcium binding ability in head and neck cancers

Li-Hao Cheng, Kai-Feng Hung, Tung-Fu Huang, Hsin-Pei Hsieh, Shu-Ying Wang, Chih-Yang Huang and Jeng-Fan Lo _

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Oncotarget. 2016; 7:78946-78957. https://doi.org/10.18632/oncotarget.12935

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Li-Hao Cheng1, Kai-Feng Hung2, Tung-Fu Huang3,4, Hsin-Pei Hsieh5, Shu-Ying Wang5, Chih-Yang Huang6,7,8, Jeng-Fan Lo1,2,6,9,10,11

1Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan

2Department of Dentistry, School of Dentistry, National Yang-Ming University, Taipei, Taiwan

3School of Medicine, National Yang-Ming University, Taipei, Taiwan

4Department of Orthopedics and Traumatology, Taipei Veterans General Hospital, Taipei, Taiwan

5Department of Microbiology and Immunology, Medical College, National Cheng Kung University, Tainan, Taiwan

6Graduate Institute of Chinese Medical Science and Institute of Medical Science, China Medical University, Taichung, Taiwan

7Institute of Basic Medical Science, China Medical University, Taichung, Taiwan

8Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan

9Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan

10Genome Research Center, National Yang-Ming University, Taipei, Taiwan

11National Yang-Ming University VGH Genome Research Center, Taipei, Taiwan

Correspondence to:

Jeng-Fan Lo, email: jflo@ym.edu.tw

Chih-Yang Huang, email: cyhuang@mail.cmu.edu.tw

Keywords: epithelial-mesenchymal transition, head and neck squamous cell carcinomas, GRP78, p53, Nanog

Received: June 03, 2016     Accepted: October 19, 2016     Published: October 26, 2016


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.

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