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Intracellular IL-37b interacts with Smad3 to suppress multiple signaling pathways and the metastatic phenotype of tumor cells

Oncogene volume 36, pages 2889–2899 (2017)Cite this article

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Abstract

Multiple signaling pathways that promote tumor cell metastasis are differentially activated in low/non-metastatic and metastatic tumor cells, resulting in the differential expression of metastasis-related genes. The underlying mechanism may involve the alterations of the intrinsic negative regulation in tumor cells. Here we report that the differential expression of interleukin-37b (IL-37b) in tumor cells alters the intrinsic negative regulation of signaling pathways, resulting in the difference of metastatic capacity. IL-37b could bind Smad3 and suppress Smad pathway by interfering with the formation and nuclear translocation of Smad2/3/4 complex. In turn, Smad3 could function as a co-regulator, enabling IL-37b to suppress multiple non-Smad pathways. IL-37b-Smad3 translocated into nucleus to upregulate the expression of non-receptor protein tyrosine phosphatases (PTPNs), thus promoting dephosphorylation to suppress the activation of tyrosine phosphorylation-dependent signaling pathways such as ERK, p38 MAPK, JNK, PI3K, NF-κB, and STAT3 pathways. Intriguingly, 13 of 17 PTPNs, most of which are metastasis suppressors, were downregulated in metastatic tumor cells because of the low expression of IL-37b. The marked decrease of intracellular IL-37b attenuated the intrinsic negative regulation in tumor cells, resulting in the enhanced activation of multiple signaling pathways and the increased capacity of invasiveness and metastatic colonization. Consistently, low expression of IL-37b in tumors was significantly associated with poor prognosis of cancer patients. Taken together, these findings reveal that intracellular IL-37b is a critical factor in the negative regulation of multiple signaling pathways that modulate the expression of metastasis-related genes, and suggest that IL-37b expression in tumor cells can potentially be a histopathological prognostic parameter for cancer patients and a therapeutic target for preventing tumor metastasis.

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Acknowledgements

We thank Zhi-Hui Liang, Hui-Fen Zhu, Sheng-Hong Liu for technical assistance; Professor Guan-Xin Shen, Xiong-Wen Wu, Xin-Xing Wu, Zhan-Qiu Yang for their valuable comments and critical review of the manuscript. This work was supported by National Natural Science Foundation of China (no. 81472704 and 30830095 to Z-HF, and 81272314 to G-MZ), and National Development Program (973) For Key Basic Research of China (no. 2009CB521806 to Z-HF).

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  1. C Luo and Y Shu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    C Luo, Y Shu, J Luo, Y-C Li, J-M Zou, J Qin, Y Wang, D Li, S-S Wang, G-M Zhang, J Chen & Z-H Feng

  2. Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    D Liu

  3. Clinical Research Institute, Zhejiang Provincial People’s Hospital, Hangzhou, People’s Republic of China

    D-S Huang & Y Han

  4. Research Institute of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, People’s Republic of China

    C Chen

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Luo, C., Shu, Y., Luo, J. et al. Intracellular IL-37b interacts with Smad3 to suppress multiple signaling pathways and the metastatic phenotype of tumor cells. Oncogene 36, 2889–2899 (2017). https://doi.org/10.1038/onc.2016.444

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