CGI-99 promotes breast cancer metastasis via autocrine interleukin-6 signaling
CGI-99 promotes breast cancer metastasis via autocrine interleukin-6 signaling
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CGI-99 通过自分泌白细胞介素 6 信号传导促进乳腺癌转移
DOI：
10.1038/onc.2016.525
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发表时间：
2017-06-29
期刊：
影响因子：
8
通讯作者：
Song, L.
中科院分区：
文献类型：
--
作者：
Lin, C.;Liao, W.;Song, L.
转移复发在很大程度上仍然是不可治愈的，是乳腺癌临床管理的主要挑战，但其潜在机制知之甚少。在此，我们报告CGI-99在5年内转移复发患者的乳腺癌组织中过表达。高CGI-99显著预测较差的5年无转移患者生存率。我们发现CGI-99增加了乳腺癌干细胞的特性，并在体内增强了有效的肿瘤肺定植和生长。此外，我们证明CGI-99通过增加RNA聚合酶II和p300辅因子在IL-6近端启动子处的积累和活性来激活自分泌白细胞介素-6（IL-6）/STAT 3信号传导。重要的是，IL-6受体人源化单克隆抗体托珠单抗的递送在体内稳健地消除CGI-99诱导的转移。最后，我们发现高水平的CGI-99与乳腺癌患者中STAT 3的过度激活显著相关。这些发现揭示了自分泌IL-6/STAT 3信号转导的组成性激活的潜在机制，并可能为乳腺癌的临床干预提供新的靶点。
Metastatic relapse remains largely incurable and a major challenge of clinical management in breast cancer, but the underlying mechanisms are poorly understood. Herein, we report that CGI-99 is overexpressed in breast cancer tissues from patients with metastatic recurrence within 5 years. High CGI-99 significantly predicts poorer 5-year metastasis-free patient survival. We find that CGI-99 increases breast cancer stem cell properties, and potentiates efficient tumor lung colonization and outgrowth in vivo. Furthermore, we demonstrate that CGI-99 activates the autocrine interleukin-6 (IL-6)/STAT3 signaling by increasing the accumulation and activity of RNA polymerase II and p300 cofactor at the proximal promoter of IL-6. Importantly, delivery of the IL-6-receptor humanized monoclonal antibody tocilizumab robustly abrogates CGI-99-induced metastasis in vivo. Finally, we find that high levels of CGI-99 are significantly correlated with STAT3 hyperactivation in breast cancer patients. These findings reveal a potential mechanism for constitutive activation of autocrine IL-6/STAT3 signaling and may suggest a novel target for clinical intervention in breast cancer.