Study On Mechanism And Significance Of Cx43Expression In Tumor Cells During Colorectal Cancer Cell-activated Fibroblast Interactions

Colorectal cancer (CRC) is one of the most malignant digestive system tumors that threaten human life. It is extremely urgent to find efficient therapeutic targets to colorectal cancer. Recent reports show that stromal cells surrounding tumor, fibroblasts in particular, play an essential role during tumor progression.Connexin43(Cx43) acts as an tumor suppressor. It is closely associated with Wnt signal, a significant regulatory sigal in colorectal cancer, and TGF-β signal, which can activate fibroblasts during tumor-stroma interactions. Epithelial-mesenchymal transition (EMT) is engaged in tumor-stroma interactions as well.Previously we found Cx43was abnormally up-regulated on the infiltration front of colorectal cancer tissue. In vitro, double-layer cell spheroid model or mixed coculture model both showed up-regulated expression of Cx43in CRC cells as well as that fibroblasts were activated.To explore the machenism and significance of up-regulated Cx43during tumor cell-fibroblast interactions, we put CRC cells and fibroblasts or artificially activated fibroblasts into double-layer coculture model. Then tumor cells were detected with the expression of Cx43, Wnt signal relative factors, TGF-β signal relative factors and EMT relative factors as well as cell proliferation and gap junction intercellular communication level. Results reveal that in early CRC cell-fibroblast coculture system, mRNA level of Cx43in CRC cell is increased and Wnt signal is also activated with facilitated cell proliferation. At late stage, elevated expression of Cx43protein in tumor cells can transfer into nucleus with β-catenin to cut off Wnt signal downstream and inhibite cell proliferation. TGF-β signal of tumor cell is also activated at late stage. Tumor cells have a tendency to EMT at early stages in coculture system but this phenomenon is reversed at late stage.From the above findings, we can get the following conclusions:1. Fibroblast-cancer cell interactions up-regulate Cx43expression in tumor cells2. Fibroblast-cancer cell interactions are phased;3. Wnt signal in tumor cells is acitivated and tumor cell proliferation is enhanced at early fibroblast-cancer cell interactions4. High expression of Cx43in tumor cells at late fibroblast-cancer cell interactions may regulate Wnt signal by a negative feedback machenism to suppress tumor cell proliferation;5. TGF-β signal of tumor cell is activated at late fibroblast-cancer cell interactions;6. Tumor cell has a tendency to EMT at early fibroblast-cancer cell interactions, which, however, is inhibited at late stage.