title: miR145 targets the SOX9/ADAM17 axis to inhibit tumor-initiating cells and IL-6-mediated paracrine effects in head and neck cancer.
abstract: ALDH1(+)CD44(+) cells are putative tumor-initiating cells (TIC) in head and neck squamous cell carcinomas (HNC). miR-145 regulates tumorigenicity in various cancers but the breadth of its mechanistic contributions and potential therapeutic applications are not completely known. Here, we report that ALDH1(+)CD44(+)-HNC cells express reduced levels of miR145. SPONGE-mediated inhibition of miR-145 (Spg-miR145) was sufficient to drive tumor-initiating characteristics in non-TICs/ALDH1(-)CD44-negative HNC cells. Mechanistic analyses identified SOX9 and ADAM17 as two novel miR145 targets relevant to this process. miR-145 expression repressed TICs in HNC in a manner associated with SOX9 interaction with the ADAM17 promoter, thereby activating ADAM17 expression. Notably, the SOX9/ADAM17 axis dominated the TIC-inducing activity of miR-145. Either miR-145 suppression or ADAM17 overexpression in non-TICs/ALDH1(-)CD44(-)-HNC cells increased expression and secretion of interleukin (IL)-6 and soluble-IL-6 receptor (sIL-6R). Conversely, conditioned medium from Spg-miR145-transfected non-TICs/ALDH1(-)CD44(-)-HNC cells was sufficient to confer tumor-initiating properties in non-TICs/ALDH1(-)CD44(-)-HNC and this effect could be abrogated by an IL-6-neutralizing antibody. We found that curcumin administration increased miR-145 promoter activity, thereby decreasing SOX9/ADAM17 expression and eliminating TICs in HNC cell populations. Delivery of lentivral-miR145 or orally administered curcumin blocked tumor progression in HNC-TICs in murine xenotransplant assays. Finally, immunohistochemical analyses of patient specimens confirmed that an miR-145(low)/SOX9(high)/ADAM17(high) phenotype correlated with poor survival. Collectively, our results show how miR-145 targets the SOX9/ADAM17 axis to regulate TIC properties in HNC, and how altering this pathway may partly explain the anticancer effects of curcumin. By inhibiting IL-6 and sIL-6R as downstream effector cytokines in this pathway, miR-145 seems to suppress a paracrine signaling pathway in the tumor microenvironment that is vital to maintain TICs in HNC.
authors.affiliation: Institute of Oral Science; School of Dentistry, Oral Medicine Research Center, Chung Shan Medical University, Taichung, Taipei, Taiwan. ccyu@csmu.edu.tw
authors.forename: Cheng-Chia
authors.initials: CC
authors.lastname: Yu
authors.forename: Lo-Lin
authors.initials: LL
authors.lastname: Tsai
authors.forename: Mong-Lien
authors.initials: ML
authors.lastname: Wang
authors.forename: Chuan-Hang
authors.initials: CH
authors.lastname: Yu
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Lo
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Chang
authors.forename: Guang-Yuh
authors.initials: GY
authors.lastname: Chiou
authors.forename: Ming-Yung
authors.initials: MY
authors.lastname: Chou
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
mesh_terms: D020413:3' Untranslated Regions; D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D015850:Interleukin-6; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D019947:Receptors, Interleukin-6; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse; D003474:Curcumin