Andrographolide impedes cancer stemness and enhances radio-sensitivity in oral carcinomas via miR-218 activation
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Po-Yu Yang1,2,4,*, Pei-Ling Hsieh3,*, Tong Hong Wang5,6,7,*, Cheng-Chia Yu1,2,3,4,*, Ming-Yi Lu1,2,3,4, Yi-Wen Liao1, Tzu-Hsin Lee1,2, Chih-Yu Peng1,2,3,4
1School of Dentistry, Chung Shan Medical University, Taichung, Taiwan
2Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan
3Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan
4Oral Medicine Center, Chung Shan Medical University, Taichung, Taiwan
5Tissue Bank, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan
6Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
7Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan
*These authors contributed equally to this work
Chih-Yu Peng, email: [email protected]
Keywords: oral squamous cell carcinomas, andrographolide, miR-218, cancer stemness
Received: October 31, 2016 Accepted: November 23, 2016 Published: December 01, 2016
Current evidence suggests that oral cancer stem cells (OCSCs) possess high tumorigenic and metastatic properties as well as chemo- and radioresistance. In this study, we demonstrated that andrographolide, the main bioactive component in the medicinal plant Andrographis, significantly reduced oncogenicity and restored radio-sensitivity of ALDH1+CD44+ OCSCs. Mechanistic studies showed that andrographolide treatment increased the expression of microRNA-218 (miR-218), leading to the downregulation of Bmi1. We showed that knockdown of miR-218 in ALDH1−CD44− non-OCSCs enhanced cancer stemness, while silencing of Bmi1 significantly counteracted it. Furthermore, we found tumor growth was reduced in mice bearing xenograft tumors after andrographolide treatment via activation of miR-218/Bmi1 axis. Together, these data demonstrated that the inhibition of tumor aggressiveness in OCSCs by andrographolide was mediated through the upregulation of miR-218, thereby reducing Bmi1 expression. These findings suggest that andrographolide may be a valuable natural compound for anti-CSCs treatment of OSCC.
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