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.

Abstract	Tumor initiating cells (TICs) possessing cancer stemness were shown to be enriched after therapy, resulting in the relapse and metastasis of head and neck squamous cell carcinomas (HNC). An effective therapeutic approach suppressing the HNC-TICs would be a potential method to improve the treatments for HNC. We observed that the treatment of silibinin (SB) dose dependently down-regulated the ALDH1 activity, CD133 positivity, stemness signatures expression, self-renewal property, and chemoresistance in ALDH1+CD44+ HNC-TICs. Using miRNA-microarray and mechanistic studies, SB increased the expression of microRNA-494 (miR-494) and both Bmi1 and ADAM10 were identified as the novel targets of miR-494. Moreover, overexpression of miR-494 results in a reduction in cancer stemness. However, knockdown of miR-494 in CD44-ALDH1- non-HNC-TICs enhanced cancer stemness and oncogenicity, while co-knockdown of Bmi1 and ADAM10 effectively reversed these phenomena. Mice model showed that SB treatment by oral gavage to xenograft tumors reduced tumor growth and prolonged the survival time of tumor-bearing mice by activation of miR-494-inhibiting Bmi1/ADAM10 expression. Survival analysis indicated that a miR494highBmi1lowADAM10low phenotype predicted a favourable clinical outcome. We conclude that the inhibition of tumor aggressiveness in HNC-TICs by SB was mediated by up-regulation miR-494, suggesting that SB would be a valuable anti-cancer drug for treatment of HNC.
Authors	Yu-Chao Chang, Chia-Ing Jan, Chih-Yu Peng, Yu-Chi Lai, Fang-Wei Hu, Cheng-Chia Yu
Journal	Oncotarget (Oncotarget) Vol. 6 Issue 27 Pg. 24002-16 (Sep 15 2015) ISSN: 1949-2553 [Electronic] United States
PMID	26090866 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	AC133 Antigen Antigens, CD BMI1 protein, human CD44 protein, human Glycoproteins Hyaluronan Receptors Isoenzymes MIRN494 microRNA, human Membrane Proteins MicroRNAs PROM1 protein, human Peptides Prom1 protein, mouse Silymarin Silybin Aldehyde Dehydrogenase 1 Family ALDH1A1 protein, human ALDH1A1 protein, mouse Retinal Dehydrogenase Polycomb Repressive Complex 1 Amyloid Precursor Protein Secretases ADAM Proteins ADAM10 Protein ADAM10 protein, human
Topics	AC133 Antigen ADAM Proteins (metabolism) ADAM10 Protein Aldehyde Dehydrogenase 1 Family Amyloid Precursor Protein Secretases (metabolism) Animals Antigens, CD (metabolism) Carcinoma, Squamous Cell (genetics, metabolism) Cell Proliferation Cell Survival Drug Resistance, Neoplasm Epithelial-Mesenchymal Transition Glycoproteins (metabolism) Head and Neck Neoplasms (genetics, metabolism) Humans Hyaluronan Receptors (metabolism) Incidence Isoenzymes (metabolism) Membrane Proteins (metabolism) Mice Mice, Inbred BALB C Mice, Nude MicroRNAs (genetics, metabolism) Neoplasm Invasiveness Neoplasm Metastasis Neoplasm Transplantation Neoplastic Stem Cells (cytology) Peptides (metabolism) Phenotype Polycomb Repressive Complex 1 (metabolism) Prognosis Retinal Dehydrogenase (metabolism) Silybin Silymarin (chemistry)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!