Suppression of miR-204 enables oral squamous cell carcinomas to promote cancer stemness, EMT traits, and lymph node metastasis
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Cheng-Chia Yu1,2,3,4, Pei-Ni Chen5,*, Chih-Yu Peng1,2,3,4,*, Chuan-Hang Yu1,2,3,4, Ming-Yung Chou1,2,3,4
1Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
2School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
3Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
4Oral Medicine Research Center, Chung Shan Medical University, Taichung, Taiwan
5Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
*These authors have contributed equally to this work
Ming-Yung Chou, e-mail: [email protected]
Chuan-Hang Yu, e-mail: [email protected]
Keywords: oral squamous cell carcinomas, miR-204, stemness, EMT, metastasis
Received: October 29, 2015 Accepted: February 05, 2016 Published: February 26, 2016
The feature of oral squamous cell carcinomas (OSCC) is commonly metastasizing to locoreginal lymph nodes, and the involvement of lymph nodes metastasis represents the one of important prognostic factors of poor clinical outcome. MicroRNAs (miRNAs) have been shown to be key players of cancer-related hallmarks including cancer stemness, EMT (epithelial-mesenchymal transition), and metastaisis. Herein we showed that OSCC-derived ALDH1+ cancer stem cells (OSCC-CSCs) express lower level of miR-204, and miR-204 over-expression suppresses cancer stemness and in vivo tumor-growth of OSCC-CSCs. miR-204 binds on their 3’UTR-regions of Slug and Sox4 and suppressing their expression in OSCC-CSCs. On the contrary, down-regulation of miR-204 significantly increased cancer stemness and the lymph nodes incidence of orthotopic animal models. Furthermore, co-knockdown with sh-Slug and sh-Sox4 synergistically rescued miR-204-supressing cancer stemness and EMT properties. Clinical results further revealed that a miR-204lowSlughighSox4high signature predicted the worse survival prognosis of OSCC patients by Kaplan-Meier survival analyses. Up-regulated miR-204-targeting Slug and Sox4 by epigallocatechin-3-gallate (EGCG) treatment significantly inhibited the proliferation rate, self-renewal capacity, and the percentage of ALDH1+ and CD44+ cells in OSCC-CSCs Oral-feeding of EGCG effectively alleviated tumor-progression in OSCC-CSCs-xenotransplanted immunocompromised mice through miR-204 activation. In conclusion, miR-204-mediated suppression of cancer stemness and EMT properties could be partially augmented by the anti-CSCs effect of EGCG.
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