Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin β3–p38 MAPK signalling

Siyang Wen, Yixuan Hou, Lixin Fu, Lei Xi, Dan Yang, Maojia Zhao, Yilu Qin, Kexin Sun, Yong Teng, Manran Liu

Research output: Contribution to journalArticle

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Abstract

Metastasis is the leading cause of breast cancer–related deaths. Cancer-associated fibroblasts (CAFs), the predominant stromal cell type in the breast tumour microenvironment, may contribute to cancer progression through interaction with tumour cells. Nonetheless, little is known about the details of the underlying mechanism. Here we found that interaction of interleukin 32 (IL32) with integrin β3 (encoded by ITGB3; a member of the integrin family) mediating the cross-talk between CAFs and breast cancer cells plays a crucial role in CAF-induced breast tumour invasiveness. IL32, an ‘RGD’ motif–containing cytokine, was found to be abundantly expressed in CAFs. Integrin β3 turned out to be up-regulated in breast cancer cells during epithelial–mesenchymal transition (EMT). CAF-derived IL32 specifically bound to integrin β3 through the RGD motif, thus activating intracellular downstream p38 MAPK signalling in breast cancer cells. This signalling increased the expression of EMT markers (fibronectin, N-cadherin, and vimentin) and promoted tumour cell invasion. Counteracting IL32 activity, a knockdown of IL32 or integrin β3 led to specific inactivation of p38 MAPK signalling in tumour cells. Blockage of the p38 MAPK pathway also diminished IL32-induced expression of EMT markers and breast cancer cell invasion and metastasis. Thus, our data indicate that CAF-secreted IL32 promotes breast cancer cell invasion and metastasis via integrin β3–p38 MAPK signalling.

Original languageEnglish (US)
Pages (from-to)320-332
Number of pages13
JournalCancer Letters
Volume442
DOIs
StatePublished - Feb 1 2019

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Interleukins
Integrins
Breast Neoplasms
Neoplasm Metastasis
p38 Mitogen-Activated Protein Kinases
Neoplasms
Tumor Microenvironment
Cancer-Associated Fibroblasts
Vimentin
Cadherins
Stromal Cells
Fibronectins
Breast
Cytokines

Keywords

  • CAF
  • IL32
  • Integrin β3
  • Tumour invasion
  • p38 MAPK

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin β3–p38 MAPK signalling. / Wen, Siyang; Hou, Yixuan; Fu, Lixin; Xi, Lei; Yang, Dan; Zhao, Maojia; Qin, Yilu; Sun, Kexin; Teng, Yong; Liu, Manran.

In: Cancer Letters, Vol. 442, 01.02.2019, p. 320-332.

Research output: Contribution to journalArticle

Wen, Siyang ; Hou, Yixuan ; Fu, Lixin ; Xi, Lei ; Yang, Dan ; Zhao, Maojia ; Qin, Yilu ; Sun, Kexin ; Teng, Yong ; Liu, Manran. / Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell invasion and metastasis via integrin β3–p38 MAPK signalling. In: Cancer Letters. 2019 ; Vol. 442. pp. 320-332.
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