The Effect Of Connexin 26 In Promoting Colorectal Cancer Liver Metastasis And Underling Mechanisms

Distant metastasis of colorectal cancer plays important role in its poor prognosis,in which liver is the most common organ.Liver metastasis is one of the leading causes of death in colorectal cancer patients with primary tumor removal.However,the mechanism of liver metastasis in colorectal cancer is still unclear.Investigating the mechanism of liver metastasis in colorectal cancer will provide new clues for the clinical diagnosis and treatment of colorectal cancer.In this article,we explored the role and possible mechanisms of connexin 26(Cx26)in liver metastasis of colorectal cancer.Anaysis of TCGA database revealed that Cx26 mRNA was upregulated in late stage colon cancer;Immunohistochemical staining of 20 pairs of primary and metastatic specimens from colon cancer patients revealed that the expression of Cx26 protein increased in metastatic foci compared to the primary one.In colon cancer cell line HCT116-LM1,which have higher liver metastatic capacity,the mRNA and protein levels of Cx26 were significantly increased.In a mouse liver metastasis model,knockdown of Cx26 expression on colon cancer can decrease their liver metastasis ability,while overexpressing Cx26 could promote colon cancer liver metastasis.Cx26 channel dead mutant C60F and gap junction inhibitor 2-APB can reverse the role of Cx26 in promoting liver metastasis of colon cancer,suggesting that the effect of Cx26 depends on the function of gap junction channels.We further explored the biological mechanism that Cx26 may affect,and the results showed that intervention with Cx26 expression did not affect colon cancer cell proliferation,migration,EMT and anoikis;immunohistochemical staining showed that in mice model,the liver metastatic foci of Cx26 overexpressed colon cancer have higher positive rate of Ki67 staining and increased blood vessel density,suggesting that in the liver microenvironment,Cx26 can promote the proliferation and angiogenesis of colon cancer cells.In summary,our research indicates that Cx26 expression is up-regulated during liver metastasis of colon cancer.Up-regulated Cx26 may modify the liver microenvironment through gap junction channel function,and promote the proliferation and angiogenesis of metastatic foci.