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Alternative NF-κB signaling promotes colorectal tumorigenesis through transcriptionally upregulating Bcl-3

Oncogene volume 37, pages 5887–5900 (2018)Cite this article

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Abstract

Multiple studies have shown that chronic inflammation is closely related to the occurrence and development of colorectal cancer (CRC). Classical NF-κB signaling, the key factor in controlling inflammation, has been found to be of great importance to CRC development. However, the role of alternative NF-κB signaling in CRC is still elusive. Here, we found aberrant constitutive activation of alternative NF-κB signaling both in CRC tissue and CRC cells. Knockdown of RelB downregulates c-Myc and upregulates p27Kip1 protein level, which inhibits CRC cell proliferation and retards CRC xenograft growth. Conversely, overexpression of RelB increases proliferation of CRC cells. In addition, we revealed a significant correlation between Bcl-3 and RelB in CRC tissues. The expression of RelB was consistent with the expression of Bcl-3 and the phosphorylation of Bcl-3 downstream proteins p-Akt (S473) and p-GSK3β (S9). Bcl-3 overexpression can restore the phenotype changes caused by RelB knockdown. Importantly, we demonstrated that alternative NF-κB transcriptional factor (p52:RelB) can directly bind to the promoter region of Bcl-3 gene and upregulate its transcription. Moreover, the expression of RelB, NF-κB2 p52, and Bcl-3 was associated with poor survival of CRC patients. Taken together, these results represent that alternative NF-κB signaling may function as an oncogenic driver in CRC, and also provide new ideas and research directions for the pathogenesis, prevention, and treatment of other inflammatory-related diseases.

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Acknowledgements

This work was supported by the National Program on Key Research (2016YFC1302400), the National Basic Research Program (2014CB541904, 2014CB943600), National Natural Science Foundation of China (91742113, 31570902, 31370881), and Natural Science Foundation of Shanghai (14ZR1426300, 18ZR1424400, 18ZR1446400).

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    Authors and Affiliations

    1. The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, 200025, China

      Yu Tao, Zhanjie Liu, Sanhong Liu, Yuhang Jiang, Cuifeng Li, Yiming Hu, Zhi Liu, Xi Chen, Qi Wang & Xiaoren Zhang

    2. Department of Pathology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China

      Yingyong Hou

    3. Department of Pathology, Soochow University School of Medicine, Suzhou, 215123, China

      Shouli Wang

    4. Shanghai Institute for Advanced Immunochemical Studies, Shanghai Tech University, Shanghai, China

      Sanhong Liu

    5. Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

      Dan Tan & Mingliang Wang

    6. Department of Obstetrics and Gynecology, The Sixth People’s Hospital Affiliated with Shanghai Jiao Tong University, Shanghai, China

      Qiulin Ge

    7. Affiliated Cancer Hospital and Institute, Guangzhou Medical University, Guangzhou, 510000, China

      Xiaoren Zhang

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    Tao, Y., Liu, Z., Hou, Y. et al. Alternative NF-κB signaling promotes colorectal tumorigenesis through transcriptionally upregulating Bcl-3. Oncogene 37, 5887–5900 (2018). https://doi.org/10.1038/s41388-018-0363-4

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