title: 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.affiliation: Department of Dentistry and Institute of Oral Biology, School of Dentistry, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Lo
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.forename: Guang-Yuh
authors.initials: GY
authors.lastname: Chiou
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chen
authors.forename: Pin-I
authors.initials: PI
authors.lastname: Huang
authors.forename: Chian-Shiu
authors.initials: CS
authors.lastname: Chien
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.forename: Pen-Yuan
authors.initials: PY
authors.lastname: Chu
authors.forename: Kai-Hsi
authors.initials: KH
authors.lastname: Lu
authors.forename: Kuo-Wei
authors.initials: KW
authors.lastname: Chang
authors.forename: Shou-Yen
authors.initials: SY
authors.lastname: Kao
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
mesh_terms: D000328:Adult; D000368:Aged; D000444:Aldehyde Dehydrogenase / Q000032:analysis; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000473:pathology / Q000556:secondary / Q000628:therapy; D002294:Carcinoma, Squamous Cell; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary / Q000628:therapy; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D007527:Isoenzymes / Q000032:analysis; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000378:metabolism; D018307:Neoplasms, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000556:secondary / Q000628:therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D050697:Retinal Dehydrogenase; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: C069077:BMI1 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D007527:Isoenzymes; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; D012097:Repressor Proteins; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase; D063150:Polycomb Repressive Complex 1