β-catenin regulates IRF3-mediated innate immune signalling in colorectal cancer.

OBJECTIVE

β-catenin is one of the most critical oncogenes associated with many kinds of human cancers, especially in the human CRC. Innate immunity recognizes tumour derived damage-associated molecular patterns (DAMPs) and primes the anti-tumour adaptive responses. While the function of β-catenin in CRC tumourigenesis is well established, its impact on innate immune evasion is largely unknown. The aim of this study is to characterize the role of β-catenin in inhibiting RIG-I-like receptor (RLR)-mediated IFN-β signalling in colorectal cancer.

MATERIALS AND METHODS

Immunohistochemical staining and western blotting were conducted to study the expression of β-catenin, IRF3 and phospho-IRF3 (p-IRF3) in CRC samples and cell lines. Plaque assay determining virus replication was performed to assess the regulation of β-catenin on IFN-β signalling. The inhibition of β-catenin on RLR-mediated IFN-β signalling was further studied by real-time analyses and reporter assays in the context of lentiviral-mediated β-catenin stably knocking down. Lastly, co-immunoprecipitation and nuclear fractionation assay were conducted to monitor the interaction between β-catenin and IRF3.

RESULTS

We found that high expression of β-catenin positively correlated with the expression of IRF3 in CRC cells. Overexpression of β-catenin increased the viral replication. Conversely knocking down of β-catenin inhibited viral replication. Furthermore, our data demonstrated that β-catenin could inhibit the expression of IFN-β and interferon-stimulated gene 56 (ISG56). Mechanistically, we found that β-catenin interacted with IRF3 and blocked its nuclear translocation.

CONCLUSION

Our study reveals an unprecedented role of β-catenin in enabling innate immune evasion in CRC.