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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264360 | GEO | 2025/12/17

REPOSITORIES: GEO

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Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.

Project description:Purpose: WNT signaling activation in colorectal cancers (CRCs) occurs mainly through APC inactivation or, more uncommonly, β-catenin activation. Both processes promote β-catenin nuclear accumulation, which transcriptionally up-regulates epithelial-to-mesenchymal transition (EMT)-related genes. Experimental Design: We investigated β-catenin localization, downstream gene expression, and phenotypic alterations in HCT116 cells containing a wild-type (HCT116-WT) or mutant β-catenin allele (HCT116-MT), or parental cells with both WT and mutant alleles (HCT116-P). We then analyzed β-catenin localization and associated phenotypes in CRC tissues. Results: Wild-type β-catenin mainly localized at the cell membrane, whereas mutant showed predominantly nuclear localization; membranous, cytoplasmic, and nuclear localization was observed in HCT116-P cells. Microarray analysis revealed significant down-regulation of Claudin-7 and E-cadherin in HCT116-MT vs. HCT116-WT cells. Claudin-7 was also down-regulated in HCT116-P vs. HCT116-WT cells, although E-cadherin expression was unaffected. Altered expression of cell-cell junction-related molecules led to tight junction (TJ) impairment in HCT116-P, and dual loss of TJs and adherens junctions (AJs) in HCT116-MT. TJ loss increased migration and invasion activities of HCT116-WT, whereas AJ loss was required to further up-regulate these activities in HCT116-P. Immunohistochemistry analysis of 101 stage III CRC tissues revealed high nuclear β-catenin expression (≥30% of tumor cells) in 15 (14.9%) samples, low nuclear expression (1-29%) in 53 (52.5%) samples, and undetectable nuclear expression in 33 (32.6%) samples, with a trend toward more frequent down-regulation of Claudin-7 and E-cadherin, and increased metastasis in CRCs with high vs. low nuclear β-catenin. Conclusions: β-catenin activation and nuclear translocation induce EMT progression by modifying cell-cell junctions, and are associated with aggressive behaviors of CRCs.

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

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