TY - JOUR
T1 - CXCL1 derived from tumor-associated macrophages promotes breast cancer metastasis via activating NF-κB/SOX4 signaling
AU - Wang, Neng
AU - Liu, Weiping
AU - Zheng, Yifeng
AU - Wang, Shengqi
AU - Yang, Bowen
AU - Li, Min
AU - Song, Juxian
AU - Zhang, Fengxue
AU - Zhang, Xiaotong
AU - Wang, Qi
AU - Wang, Zhiyu
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (Grant Nos. 81573651, 81703749 and 81703764), the Guangdong Science and Technology Department (Grant Nos. 2016A030306025), the PhD Start-up Fund of Natural Science Foundation of Guangdong Province (Grants Nos. 2017A030310213), the Pearl River S&T Nova Program of Guangzhou (Grant Nos. 201506010098), the Combined Scientific Project Funded by Guangdong Provincial Science and Technology Agency and Guangdong Provincial Academy of Traditional Chinese Medicine (Grant Nos. 2014A020221047), the Guangdong High-Level University Construction Project (Grant Nos. A1-AFD018161Z1510, A1-AFD01817Z11102, A1-AFD01817Z11101), the Guangdong High-Level Personnel of Special Support Program (Grant Nos. A1-3002-16-111-003), the Guangdong Traditional Chinese Medicine bureau project (Grants Nos. 20181132 and 20182044), the Post-Doctoral Science Foundation of China (Grants Nos. 2017M612644 and 2017M622669) and the International Post-Doctoral Exchange Fellowship Program & China PostDoctoral Science Foundation (Grant Nos. 2016M592585). We would also like to thank LetPub (www.letpub.com) for providing linguistic assistance during the preparation of this manuscript.
PY - 2018/8/29
Y1 - 2018/8/29
N2 - Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and multiple TAM-secreted cytokines have been identified associating with poor clinical outcomes. However, the therapeutic targets existing in the loop between TAMs and cancer cells are still required for further investigation. Here in, cytokine array validated that C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant chemokine secreted by TAMs, and CXCL1 can promote breast cancer migration and invasion ability, as well as epithelial–mesenchymal transition in both mouse and human breast cancer cells. QPCR screening further validated SOX4 as the highest responsive gene following CXCL1 administration. Mechanistic study revealed that CXCL1 binds to SOX4 promoter and activates its transcription via NF-κB pathway. In vivo breast cancer xenografts demonstrated that CXCL1 silencing in TAMs results in a significant reduction in breast cancer growth and metastatic burden. Bioinformatic analysis and clinical investigation finally suggested that high CXCL1 expression is significantly correlated with breast cancer lymph node metastasis, poor overall survival and basal-like subtype. Taken together, our results indicated that TAMs/CXCL1 promotes breast cancer metastasis via NF-κB/SOX4 activation, and CXCL1-based therapy might become a novel strategy for breast cancer metastasis prevention.
AB - Tumor-associated macrophages (TAMs) have been implicated in the promotion of breast cancer growth and metastasis, and multiple TAM-secreted cytokines have been identified associating with poor clinical outcomes. However, the therapeutic targets existing in the loop between TAMs and cancer cells are still required for further investigation. Here in, cytokine array validated that C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant chemokine secreted by TAMs, and CXCL1 can promote breast cancer migration and invasion ability, as well as epithelial–mesenchymal transition in both mouse and human breast cancer cells. QPCR screening further validated SOX4 as the highest responsive gene following CXCL1 administration. Mechanistic study revealed that CXCL1 binds to SOX4 promoter and activates its transcription via NF-κB pathway. In vivo breast cancer xenografts demonstrated that CXCL1 silencing in TAMs results in a significant reduction in breast cancer growth and metastatic burden. Bioinformatic analysis and clinical investigation finally suggested that high CXCL1 expression is significantly correlated with breast cancer lymph node metastasis, poor overall survival and basal-like subtype. Taken together, our results indicated that TAMs/CXCL1 promotes breast cancer metastasis via NF-κB/SOX4 activation, and CXCL1-based therapy might become a novel strategy for breast cancer metastasis prevention.
UR - http://www.scopus.com/inward/record.url?scp=85052673769&partnerID=8YFLogxK
U2 - 10.1038/s41419-018-0876-3
DO - 10.1038/s41419-018-0876-3
M3 - Article
C2 - 30158589
AN - SCOPUS:85052673769
SN - 2041-4889
VL - 9
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 9
M1 - 880
ER -