Cancer-associated fibroblast-derived interleukin-1β activates protumor C-C motif chemokine ligand 22 signaling in head and neck cancer

Yu Hsuan Huang, Che Ying Chang, Yi Zih Kuo, Wei Yu Fang, Hung Ying Kao, Sen-Tien Tsai, Li-Wha Wu

Research output: Contribution to journalArticle

Abstract

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1β (IL-1β) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1β, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1β-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.

Original languageEnglish
Pages (from-to)2783-2793
Number of pages11
JournalCancer Science
Volume110
Issue number9
DOIs
Publication statusPublished - 2019 Sep 1

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CC Chemokines
Head and Neck Neoplasms
Interleukin-1
Ligands
Mouth Neoplasms
Messenger RNA
Regulatory T-Lymphocytes
Cell Movement
CCR4 Receptors
Carcinogenesis
Cancer-Associated Fibroblasts
Activating Transcription Factors
Cell Proliferation
NF-kappa B
Disease-Free Survival
Disease Progression
Cultured Cells

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Huang, Yu Hsuan ; Chang, Che Ying ; Kuo, Yi Zih ; Fang, Wei Yu ; Kao, Hung Ying ; Tsai, Sen-Tien ; Wu, Li-Wha. / Cancer-associated fibroblast-derived interleukin-1β activates protumor C-C motif chemokine ligand 22 signaling in head and neck cancer. In: Cancer Science. 2019 ; Vol. 110, No. 9. pp. 2783-2793.
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Cancer-associated fibroblast-derived interleukin-1β activates protumor C-C motif chemokine ligand 22 signaling in head and neck cancer. / Huang, Yu Hsuan; Chang, Che Ying; Kuo, Yi Zih; Fang, Wei Yu; Kao, Hung Ying; Tsai, Sen-Tien; Wu, Li-Wha.

In: Cancer Science, Vol. 110, No. 9, 01.09.2019, p. 2783-2793.

Research output: Contribution to journalArticle

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T1 - Cancer-associated fibroblast-derived interleukin-1β activates protumor C-C motif chemokine ligand 22 signaling in head and neck cancer

AU - Huang, Yu Hsuan

AU - Chang, Che Ying

AU - Kuo, Yi Zih

AU - Fang, Wei Yu

AU - Kao, Hung Ying

AU - Tsai, Sen-Tien

AU - Wu, Li-Wha

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N2 - Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1β (IL-1β) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1β, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1β-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.

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