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CGI-99 promotes breast cancer metastasis via autocrine interleukin-6 signaling

Oncogene volume 36, pages 3695–3705 (2017)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by the Ministry of Science and Technology of China grant (no. 973-2014CB910604); Natural Science Foundation of China (no. 81472546, 81672854, 81530082, 81272198, 81572687, 81325013, 91529301 and 81572688), the Science and Technology of Guangdong Province (no. 2016A030308002, 2014A030313008 and 2014A030313220), Science and Technology Program of Guangzhou (no. 15020077) and Guangdong Esophageal Cancer Institute (no. M201409).

Author contributions

CL, YJ and WL carried out most of the experimental work. CL and YJ conducted enzyme-linked immunosorbent assay analysis and animal experiments. WL and LY conducted immunohistochemistry analysis and cell experiments. YP, XZ and BW conducted western blot analysis. YC conducted PCR. ZX, XW and SW conducted the molecular cloning and luciferase assay. JL, XW and LS supervised the project and wrote the manuscript.

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Author notes

  1. C Lin, W Liao and Y Jian: These three authors contributed equally to this work.

Authors and Affiliations

  1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China

    C Lin, X Zhang, L Ye, Y Cui, B Wang, X Wu, S Wu & L Song

  2. Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, China

    W Liao & Y Jian

  3. Guangdong Country Garden school, Guangzhou, China

    Y Peng

  4. Department of Breast Surgery, Cancer Center, Sun Yat-sen University, Guangzhou, China

    Z Xiong & X Wang

  5. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China

    J Li

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Lin, C., Liao, W., Jian, Y. et al. CGI-99 promotes breast cancer metastasis via autocrine interleukin-6 signaling. Oncogene 36, 3695–3705 (2017). https://doi.org/10.1038/onc.2016.525

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