Activation of microRNA-494-targeting Bmi1 and ADAM10 by silibinin ablates cancer stemness and predicts favourable prognostic value in head and neck squamous cell carcinomas

摘要: // Yu-Chao Chang 1,2,4 , Chia-Ing Jan 5,6,* Chih-Yu Peng 1,2,4,* Yu-Chi Lai 3 Fang-Wei Hu 1,2,3,4 and Cheng-Chia Yu 1 School of Dentistry, Chung Shan Medical University, Taichung, Taiwan 2 Department University Hospital, Institute Oral Sciences, 4 Medicine Research Center, 5 Pathology, China 6 Beigang Yunlin, * These authors contributed equally to this work Correspondence to: Yu, email: Hu, Keywords : head neck squamous cell carcinomas, tumor initiating cells, silibinin, microRNA-494 Received February 26, 2015 Accepted May 30, Published June 08, Abstract Tumor cells (TICs) possessing cancer stemness were shown be enriched after therapy, resulting in the relapse metastasis carcinomas (HNC). An effective therapeutic approach suppressing HNC-TICs would a potential method improve treatments for HNC. We observed that treatment silibinin (SB) dose dependently down-regulated ALDH1 activity, CD133 positivity, signatures expression, self-renewal property, chemoresistance ALDH1+CD44+ HNC-TICs. Using miRNA-microarray mechanistic studies, SB increased expression (miR-494) both Bmi1 ADAM10 identified as novel targets miR-494. Moreover, overexpression miR-494 results reduction stemness. However, knockdown CD44 − - non-HNC-TICs enhanced oncogenicity, while co-knockdown effectively reversed these phenomena. Mice model showed by oral gavage xenograft tumors reduced growth prolonged survival time tumor-bearing mice activation miR-494-inhibiting Bmi1/ADAM10 expression. Survival analysis indicated miR494 high low phenotype predicted favourable clinical outcome. conclude inhibition aggressiveness was mediated up-regulation miR-494, suggesting valuable anti-cancer drug