Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer
Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer
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STAT3 的激活参与人类乳腺癌中 CXCL12-CXCR4 信号传导介导的恶性肿瘤
DOI：
10.3892/or.2014.3536
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发表时间：
2014-12-01
期刊：
影响因子：
4.2
通讯作者：
Wei, Minjie
中科院分区：
文献类型：
--
作者：
Liu, Xiaojian;Xiao, Qinghuan;Wei, Minjie
趋化因子受体CXCR 4和信号转导子及转录激活子3（STAT 3）在乳腺癌的恶性和转移中起重要作用。然而，在人类乳腺癌中STAT 3是否可以被CXCR 4激活仍然是未知的。采用免疫组化法检测208例乳腺癌组织和26例癌旁组织中CXCR 4、STAT 3和p-STAT 3的表达水平。采用流式细胞术、蛋白质印迹分析和免疫沉淀法研究人乳腺癌细胞系中CXCL 12-CXCR 4信号转导对STAT 3的激活作用。CXCR 4、STAT 3和p-STAT 3的表达水平在乳腺癌样品中高于肿瘤相邻样品中的这些水平。CXCR 4和p-STAT 3的联合表达与乳腺癌的TNM分期、肿瘤大小、淋巴结转移和组织学分级有关。在乳腺癌细胞中，CXCL 12处理增加了p-STAT 3的表达。CXCR 4拮抗剂AMD 3100和Janus激酶2（JAK 2）拮抗剂AG 490抑制CXCL 12诱导的STAT 3磷酸化增加。此外，CXCL 12促进JAK 2与CXCR 4的直接结合。我们的研究结果表明，JAK 2/STAT 3通路通过CXCL 12-CXCR 4信号转导的激活在乳腺癌恶性和转移中起着重要作用。靶向CXCL 12-CXCR 4/JAK 2/STAT 3信号通路可能是治疗乳腺癌的潜在治疗策略。
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.