期刊
CANCER RESEARCH
卷 73, 期 11, 页码 3425-3440出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-12-3840
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资金
- National Science Council [NSC100-2314-B-040-001, NSC100-2314-B-040-010-MY3, NSC100-2632-B-040-001-MY3, NSC100/101-2120-M-002-011, 101-2325-B-010-009, 100/101-2321-B-010-020, 101-2628-B-010-002, 100-2321-B-039-004]
- Taipei Veterans General Hospital [E99-101]
- Yen-Tjing-Ling Medical Foundation [CI-99/100]
- Department of Health Cancer Center Research of Excellence [DOH101-TD-C-111-007]
- National Health Research Institutes [NHRI-EX102-10258SI]
- Genomic Center Project of National Yang-Ming University (Ministry of Education, Aim for the Top University Plan), Taiwan
- Cancer Center Project of National Yang-Ming University (Ministry of Education, Aim for the Top University Plan), Taiwan
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. (C) 2013 AACR.
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