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

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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Correspondence to Mingliang Wang or Xiaoren Zhang.

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These authors contributed equally: Yu Tao, Zhanjie Liu, Yingyong Hou.

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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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