Funding br Conflicts of interest br The authors declare
Conflicts of interest
The authors declare no conflicts of interest.
Shin Kibe, Kenoki Ohuchida, Yohei Ando, Shin Takesue, Hiromichi Nakayama, Toshiya Abe, Sho Endo, Kazuhiro Koikawa, Takashi Okumura, Chika Iwamoto, Koji Shindo, Taiki Moriyama, Kohei Nakata, Yoshihiro Miyasaka, Masaya Shimamoto, Takao Ohtsuka, Kazuhiro Mizumoto, Yoshinao Oda, Masafumi Nakamura.
The authors thank E. Manabe, S. Sadatomi, N. Torada (Department of Surgery and Oncology, Kyushu University Hospital), and members of the Research Support Center and Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University for their expert technical assistance. The authors also thank A. Doi (Cell Innovator Co., Ltd., Fukuoka, Japan) for assistance with the gene expression analysis. We thank James Monypenny, PhD, from Edanz Group (www. edanzediting.com/ac) for editing a draft of this manuscript.
Appendix A. Supplementary data
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Cancer-associated fibroblast (CAF)-derived IL32 promotes breast cancer cell T invasion and metastasis via integrin β3–p38 MAPK signalling
Siyang Wena, Yixuan Houa,b, Lixin Fua, Lei Xia, Dan Yanga, Maojia Zhaoa, Yilu Qina, Kexin Suna, Yong Tengc, Manran Liua,∗ a Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China
b Experimental Teaching Center of Basic Medicine Science, Chongqing Medical University, Chongqing, 400016, China
c Department of Oral Biology, Dental College of Georgia, Georgia Cancer Center, Augusta University, Augusta, GA, USA
IL32 Integrin β3 p38 MAPK
Metastasis is the leading cause of breast cancer–related deaths. Cancer-associated fibroblasts (CAFs), the pre-dominant 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 me-chanism. 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–mesench-ymal transition (EMT). CAF-derived IL32 specifically bound to integrin β3 through the RGD motif, thus acti-vating intracellular downstream p38 MAPK signalling in breast cancer cells. This signalling increased the ex-pression 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 sig-nalling 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.
It has been well established that a tumour microenvironment is an active participant in the process of cancer progression [1–3]. Activated stromal cells [usually named as cancer-associated fibroblasts (CAFs) or myofibroblasts] are the major components in the tumour micro-environment [4,5]. Compared with normal fibroblasts (NFs), CAFs overexpress some biomarker proteins, such as α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), platelet-derived growth factor receptor α or β (PDGFR-α/β), or S100 calcium-binding protein A4 (S100A4), depend on the tumour type . Generally, the cross-talk between CAFs and tumour cells contributes to tumour progression mainly via a release of various secretory proteins (e.g. TGF-β, IGF, and IL6), direct interactions with tumour cells, immune-response regula-tion, and extracellular matrix (ECM) remodelling .
Integrins belong to the transmembrane protein family and act as cell surface receptors that mediate cell–cell and cell–ECM adhesion .