title: MicroRNA let-7a represses chemoresistance and tumourigenicity in head and neck cancer via stem-like properties ablation.
abstract: Head and neck cancer (HNC) is a prevalent cancer worldwide. Let-7 has been shown to function as a tumour suppressor by regulating multiple oncogenic signalling pathways. However, the role of let-7 in head and neck cancer (HNC) and in HNC-associated tumour initiating cells (TIC) remains unclear. In this study, we first demonstrated that let-7a expression was significantly decreased but that Nanog/Oct4 expression was increased in HNC tissues as compared to adjacent normal cells. Expression of let-7a in recurrent HNC tissue and in regional metastatic lymph nodes of HNC patients was also significantly decreased, but Nanog/Oct4 expression was increased as compared to the expression levels in the parental tumours. Consistently, the stemness genes were significantly up-regulated and let-7a was down-regulated in HNC-ALDH1(+) cells relative to HNC-ALDH1(-) cells. Furthermore, lentiviral-mediated let-7a overexpression could significantly inhibit the stemness signature and the chemoresistant abilities of HNC-ALDH1(+) cells. Most importantly, overexpression of let-7 or knockdown of Nanog in ALDH1(+) cells effectively blocked tumour metastasis and significantly prolonged survival time in ALDH1(+)-transplanted immunocompromised mice. Overall, restoration of let-7a in HNC and HNC-TIC may be a new approach for the therapeutic treatment of HNC in the future. These results show that let-7a negatively modulates the expression of stemness genes and plays a role as a tumour suppressor in HNC by eliminating the putative HNC-TIC population.
authors.affiliation: Institute of Oral Biology and Biomaterial Science, Chung Shan Medical University, Taichung, Taiwan. ccyu@csmu.edu.tw
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Chen
authors.forename: Guang-Yuh
authors.initials: GY
authors.lastname: Chiou
authors.forename: Lo-Lin
authors.initials: LL
authors.lastname: Tsai
authors.forename: Pin-I
authors.initials: PI
authors.lastname: Huang
authors.forename: Charn-Yung
authors.initials: CY
authors.lastname: Chang
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Sang-Hue
authors.initials: SH
authors.lastname: Yen
authors.forename: Ming-Yung
authors.initials: MY
authors.lastname: Chou
authors.forename: Pen-Yuan
authors.initials: PY
authors.lastname: Chu
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Lo
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D013624:Taiwan
chemical_list: D018398:Homeodomain Proteins; D035683:MicroRNAs; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C487931:mirnlet7 microRNA, human