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

J Pathol. 2011 Mar;223(4):482-95. doi: 10.1002/path.2826. Epub 2011 Jan 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aldehyde Dehydrogenase / analysis
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Carcinoma / genetics
  • Carcinoma / pathology
  • Carcinoma / secondary
  • Carcinoma / therapy
  • Carcinoma, Squamous Cell
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Cell Transformation, Neoplastic / metabolism
  • Female
  • Gene Expression Regulation, Neoplastic / physiology
  • Genetic Therapy / methods
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / secondary
  • Head and Neck Neoplasms / 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
  • Neoplasms, Squamous Cell / pathology
  • Neoplasms, Squamous Cell / secondary
  • Neoplasms, Squamous Cell / therapy
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Neoplastic Stem Cells / radiation effects
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Polycomb Repressive Complex 1
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA, Neoplasm / genetics*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Retinal Dehydrogenase
  • Squamous Cell Carcinoma of Head and Neck
  • Xenograft Model Antitumor Assays

Substances

  • 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