Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer

Liu,Xiaojian; Xiao,Qinghuan; Bai,Xuefeng; Yu,Zhaojin; Sun,Mingli; Zhao,Haishan; Mi,Xiaoyi; Wang,Enhua; Yao,Weifan; Jin,Feng; Zhao,Lin; Ren,Jie; Wei,Minjie

doi:10.3892/or.2014.3536

Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer

Authors:
- Xiaojian Liu
- Qinghuan Xiao
- Xuefeng Bai
- Zhaojin Yu
- Mingli Sun
- Haishan Zhao
- Xiaoyi Mi
- Enhua Wang
- Weifan Yao
- Feng Jin
- Lin Zhao
- Jie Ren
- Minjie Wei
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Affiliations: Department of Pharmacology, China Medical University, Shenyang, Liaoning 110001, P.R. China, Department of Pathology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning 110001, P.R. China, Department of Surgical Oncology, The First Afﬁliated Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
Published online on: October 10, 2014 https://doi.org/10.3892/or.2014.3536
Pages: 2760-2768

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Abstract

The chemokine receptor CXCR4 and signal transducer and activator of transcription 3 (STAT3) play an important role in breast cancer malignancy and metastasis. However, it remains unknown whether STAT3 can be activated by CXCR4 in human breast cancer. The expression levels of CXCR4, STAT3 and p-STAT3 in 208 breast cancer tissues and 26 tumor-adjacent tissues were examined by immunohistochemistry. Flow cytometry, western blot analysis and immunoprecipitation were used to study activation of STAT3 by CXCL12-CXCR4 signaling in human breast cancer cell lines. The expression levels of CXCR4, STAT3 and p-STAT3 were higher in the breast cancer samples than these levels in the tumor-adjacent samples. The combined expression of CXCR4 and p-STAT3 was correlated with TNM stage, tumor size, lymph node metastasis and histological grade of breast cancer. In the breast cancer cells, CXCL12 treatment increased the expression of p-STAT3. The CXCR4 antagonist AMD3100 and the Janus kinase 2 (JAK2) antagonist AG490 inhibited the CXCL12-induced increase in the phosphorylation of STAT3. Furthermore, CXCL12 promoted direct binding of JAK2 to CXCR4. Our findings suggest that activation of the JAK2/STAT3 pathway via CXCL12-CXCR4 signaling plays an important role in breast cancer malignancy and metastasis. Targeting the CXCL12-CXCR4/JAK2/STAT3 signaling pathway may be a potential therapeutic strategy for the treatment of breast cancer.

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