MiR145 targets the SOX9/ADAM17 axis to inhibit tumor-initiating cells and IL-6-mediated paracrine effects in head and neck cancer

Cheng Chia Yu, Lo Lin Tsai, Mong Lien Wang, Chuan Hang Yu, Wen Liang Lo, Yun Ching Chang, Guang Yuh Chiou, Ming Yung Chou, Shih Hwa Chiou

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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 SpgmiR145- 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-145low/SOX9high/ADAM17high 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.

Original languageEnglish
Pages (from-to)3425-3440
Number of pages16
JournalCancer Research
Volume73
Issue number11
DOIs
Publication statusPublished - Jun 1 2013
Externally publishedYes

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Neoplastic Stem Cells
Head and Neck Neoplasms
Interleukin-6
Curcumin
Interleukin-6 Receptors
Neoplasms
Paracrine Communication
Tumor Microenvironment
Conditioned Culture Medium
ADAM17 Protein
Neutralizing Antibodies
aldehyde dehydrogenase 1
Cytokines
Phenotype
Survival
Population

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

MiR145 targets the SOX9/ADAM17 axis to inhibit tumor-initiating cells and IL-6-mediated paracrine effects in head and neck cancer. / Yu, Cheng Chia; Tsai, Lo Lin; Wang, Mong Lien; Yu, Chuan Hang; Lo, Wen Liang; Chang, Yun Ching; Chiou, Guang Yuh; Chou, Ming Yung; Chiou, Shih Hwa.

In: Cancer Research, Vol. 73, No. 11, 01.06.2013, p. 3425-3440.

Research output: Contribution to journalArticle

Yu, Cheng Chia ; Tsai, Lo Lin ; Wang, Mong Lien ; Yu, Chuan Hang ; Lo, Wen Liang ; Chang, Yun Ching ; Chiou, Guang Yuh ; Chou, Ming Yung ; Chiou, Shih Hwa. / MiR145 targets the SOX9/ADAM17 axis to inhibit tumor-initiating cells and IL-6-mediated paracrine effects in head and neck cancer. In: Cancer Research. 2013 ; Vol. 73, No. 11. pp. 3425-3440.
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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 SpgmiR145- 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-145low/SOX9high/ADAM17high 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.",
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AU - Yu, Cheng Chia

AU - Tsai, Lo Lin

AU - Wang, Mong Lien

AU - Yu, Chuan Hang

AU - Lo, Wen Liang

AU - Chang, Yun Ching

AU - Chiou, Guang Yuh

AU - Chou, Ming Yung

AU - Chiou, Shih Hwa

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N2 - 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 SpgmiR145- 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-145low/SOX9high/ADAM17high 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.

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