Nuclear translocation of Cx43 promotes CRC progression by CAF via activating β-catenin through TGF-β and phosphorylation

The tumor microenvironment (TME) significantly influences intercellular communication, wherein a lot of secreted factors are known to activate both tumor cells and fibroblasts. Connexin43 (Cx43), a critical gap junction protein, is recognized for its regulatory role in tumorigenesis. However, the underlying regulation mechanisms of Cx43 in colorectal cancer (CRC) is not fully understood. Here, we systematically identified Cx43 as a promoter in CRC carcinogenesis. We found that Wnt signaling pathway was activated in the co-culture of CRC cells and fibroblasts. Concurrently, we noted an upregulation of Cx43 expression, which was subsequently confirmed as a pro-oncogenic factor through survival prognostic analysis of patient samples. Intriguingly, nuclear translocation of Cx43 occurred during malignant progression and had a significant effect in metastasis and being regulated by secreted TGF-β. This process involves the interaction between Cx43 with β-catenin, facilitating the nuclear translocation of β-catenin and consequently activating the Wnt signaling pathway. Furthermore, we found different situation on nuclear translocation of Cx43 in different CRC cell lines, which determined by S368 phosphorylation. Collectively, these findings highlight the novel mechanism of nuclear translocation of Cx43 as a pro-carcinogenic factor in CRC and enhancing our understanding of the interplay between TME and CRC progression.