Research Papers:

Defective CFTR- β-catenin interaction promotes NF-κB nuclear translocation and intestinal inflammation in cystic fibrosis

Kaisheng Liu, Xiaohu Zhang, Jie Ting Zhang, Lai Ling Tsang, Xiaohua Jiang and Hsiao Chang Chan _

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Oncotarget. 2016; 7:64030-64042. https://doi.org/10.18632/oncotarget.11747

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Kaisheng Liu1,*, Xiaohu Zhang1,3,*, Jie Ting Zhang1, Lai Ling Tsang1, Xiaohua Jiang1,2, Hsiao Chang Chan1,2,3

1Epithelial Cell Biology Research Center, Key Laboratory for Regenerative Medicine of the Ministry of Education of China, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, PR China

2School of Biomedical Sciences Core Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, PR China

3Sichuan University-The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Chengdu, PR China

*These authors contributed equally to this work

Correspondence to:

Hsiao Chang Chan, email: [email protected]

Xiaohua Jiang, email: [email protected]

Keywords: CFTR, β-catenin, NF-κB, small intestine, inflammation

Received: March 29, 2016     Accepted: August 24, 2016     Published: August 31, 2016


While inflammation with aberrant activation of NF-κB pathway is a hallmark of cystic fibrosis (CF), the molecular mechanisms underlying the link between CFTR defect and activation of NF-κB-mediated pro-inflammatory response remain elusive. Here, we investigated the link between CFTR defect and NF-κB activation in ΔF508cftr−/− mouse intestine and human intestinal epithelial cell lines. Our results show that the NF-κB/COX-2/PGE2 pathway is activated whereas the β-catenin pathway is suppressed in CF mouse intestine and CFTR-knockdown cells. Activation of β-catenin pathway by GSK3 inhibitors suppresses CFTR mutation/knockdown-induced NF-κB/COX-2/PGE2 pathway in ΔF508 mouse intestine and CFTR-knockdown cells. In contrast, suppression of β-catenin signaling induces the nuclear translocation of NF-κB. In addition, CFTR co-localizes and interacts with β-catenin while CFTR mutation disrupts the interaction between NF-κB and β-catenin in mouse intestine. Treatment with proteasome inhibitor MG132 completely reverses the reduced expression of β-catenin in Caco-2 cells. Collectively, these results indicate that CFTR stabilizes β-catenin and prevents its degradation, defect of which results in the activation of NF-κB-mediated inflammatory cascade. The present study has demonstrated a previously unsuspected interaction between CFTR and β-catenin that regulates NF-κB nuclear translocation in mouse intestine. Therefore, our study provides novel insights into the physiological function of CFTR and pathogenesis of CF-related diseases in addition to the NF-κB-mediated intestinal inflammation seen in CF.

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