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MicroRNA‐200c attenuates tumour growth and metastasis of presumptive head and neck squamous cell carcinoma stem cells
Author(s) -
Lo WenLiang,
Yu ChengChia,
Chiou GuangYuh,
Chen YiWei,
Huang PinI,
Chien ChianShiu,
Tseng LingMing,
Chu PenYuan,
Lu KaiHsi,
Chang KuoWei,
Kao ShouYen,
Chiou ShihHwa
Publication year - 2011
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2826
Subject(s) - bmi1 , cd44 , head and neck squamous cell carcinoma , cancer stem cell , gene knockdown , cancer research , metastasis , microrna , epithelial–mesenchymal transition , stem cell , cancer , biology , cell , medicine , pathology , cell culture , head and neck cancer , microbiology and biotechnology , gene , biochemistry , genetics
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. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.