MicroRNA-200c attenuates tumour growth and metastasis of presumptive head and neck squamous cell carcinoma stem cells.

Abstract

MicroRNA-200c (miR200c) is emerging as an important regulator of tumourigenicity and cancer metastasis with a strong capacity for inducing epithelial-mesenchymal transitions. However, the role of miR200c in head and neck squamous cell carcinoma (HNSCC) and HNSCC-associated cancer stem cells (HNSCC-CSCs) is unknown. In this study, the expression of miR200c in the regional metastatic lymph node of HNSCC tissues was significantly decreased, but BMI1 expression was increased as compared to parental tumours. Importantly, site-directed mutagenesis with a luciferase reporter assay showed that miR200c targeted the 3' UTR of BMI1 in HNSCC cells. Isolated HNSCC-derived ALDH1(+) /CD44(+) cells displayed CSC-like tumour initiating and radio-resistant properties. The expression levels of miR200c were significantly down-regulated while BMI1 was increased in HNSCC-ALDH1(+) /CD44(+) compared to the other subsets of HNSCC cells. Furthermore, increased miR200c expression or knockdown of BMI1 could significantly inhibit the malignant CSC-like properties of ALDH1(+) /CD44(+) cells. miR200c over-expression further down-regulated the expressions of ZEB1, Snail and N-cadherin, but up-regulated E-cadherin expression in ALDH1(+) /CD44(+) cells. Finally, a xenotransplantion study confirmed that over-expression of miR200c or BMI1 knockdown effectively inhibited the lung metastatic ability and prolonged the survival rate of ALDH1(+) /CD44(+) -transplanted mice. In summary, miR200c negatively modulates the expression of BMI1 but also significantly inhibits the metastatic capability of epithelial-mesenchymal transitions in malignant HNSCC by reducing the expression of BMI1/ZEB1. Restoration of miR200c in HNSCC and CSCs may be a promising therapeutic approach.

• Authors: Wen-Liang Lo, Cheng-Chia Yu, Guang-Yuh Chiou, Yi-Wei Chen, Pin-I Huang, Chian-Shiu Chien, Ling-Ming Tseng, Pen-Yuan Chu, Kai-Hsi Lu, Kuo-Wei Chang, Shou-Yen Kao, Shih-Hwa Chiou
• Journal: The Journal of pathology (J Pathol) Vol. 223 Issue 4 Pg. 482-95 (Mar 2011) ISSN: 1096-9896 [Electronic] England
• PMID: 21294122 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• BMI1 protein, human
• CD44 protein, human
• Hyaluronan Receptors
• Isoenzymes
• MIRN200 microRNA, human
• MicroRNAs
• Neoplasm Proteins
• Nuclear Proteins
• Proto-Oncogene Proteins
• RNA, Neoplasm
• Repressor Proteins
• Aldehyde Dehydrogenase 1 Family
• Aldehyde Dehydrogenase
• ALDH1A1 protein, human
• ALDH1A1 protein, mouse
• Retinal Dehydrogenase
• Polycomb Repressive Complex 1

Topics

• Adult
• Aged
• Aldehyde Dehydrogenase (analysis)
• Aldehyde Dehydrogenase 1 Family
• Animals
• Carcinoma (genetics, pathology, secondary, therapy)
• Carcinoma, Squamous Cell
• Cell Survival (drug effects, radiation effects)
• Cell Transformation, Neoplastic (metabolism)
• Female
• Gene Expression Regulation, Neoplastic (physiology)
• Genetic Therapy (methods)
• Head and Neck Neoplasms (genetics, pathology, secondary, therapy)
• Humans
• Hyaluronan Receptors (analysis)
• Isoenzymes (analysis)
• Lymphatic Metastasis
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• MicroRNAs (genetics)
• Middle Aged
• Mutagenesis, Site-Directed
• Neoplasm Proteins (metabolism)
• Neoplasms, Squamous Cell (genetics, pathology, secondary, therapy)
• Neoplastic Stem Cells (drug effects, metabolism, pathology, radiation effects)
• Nuclear Proteins (genetics, metabolism)
• Polycomb Repressive Complex 1
• Proto-Oncogene Proteins (genetics, metabolism)
• RNA, Neoplasm (genetics)
• Repressor Proteins (genetics, metabolism)
• Retinal Dehydrogenase
• Squamous Cell Carcinoma of Head and Neck
• Xenograft Model Antitumor Assays