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Oncogene. 2018 Nov;37(44):5887-5900. doi: 10.1038/s41388-018-0363-4. Epub 2018 Jul 4.

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

Author information

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.
2
Department of Pathology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
3
Department of Pathology, Soochow University School of Medicine, Suzhou, 215123, China.
4
Shanghai Institute for Advanced Immunochemical Studies, Shanghai Tech University, Shanghai, China.
5
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
6
Department of Obstetrics and Gynecology, The Sixth People's Hospital Affiliated with Shanghai Jiao Tong University, Shanghai, China.
7
Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. mingliang-99@hotmail.com.
8
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. xrzhang@sibs.ac.cn.
9
Affiliated Cancer Hospital and Institute, Guangzhou Medical University, Guangzhou, 510000, China. xrzhang@sibs.ac.cn.

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.

PMID:
29973688
DOI:
10.1038/s41388-018-0363-4
[Indexed for MEDLINE]

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