ABERRANT EXPRESSION OF GAP JUNCTION PROTEINS (CONNEXINS) IS ASSOCIATED WITH TUMOR PROGRESSION DURING MULTISTAGE MOUSE SKIN CARCINOGENESIS IN-VIVO

To elucidate what changes in the expression of gap junction proteins ( connexins) occur at what stages during multistage mouse skin carcinoge nesis in vivo, we immunohistochemically and morphometrically analyzed the expression of connexin 26 (Cx26) and connexin 43 (Cx43) in papillo mas, well-, moderately- and poorly-differentiated squamous cell carcin omas, as well as in squamous cell carcinomas at invasion sites and tho se metastasized into lymph nodes in female CD-1 mice as a result of tr eatment with dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-1 3-acetate. In papillomas, no clear reduction of the two connexins was observed; however, Cx26 and Cx43 were frequently co-localized in the s ame gap junction plaques, whereas the two kinds of Cxs were differenti ally expressed in normal and surrounding nontumorous epidermis. In squ amous cell carcinomas, the expression of both Cx26 and Cx43 significan tly decreased compared with surrounding non-tumorous epidermis and pap illomas. The Western blot analysis confirmed that both Cx26 and Cx43 p roteins were reduced in squamous cell carcinomas compared with papillo mas. Furthermore, the expression of Cx26 was reduced as cancer cells b ecame morphologically less differentiated, while that of Cx43 did not change. Squamous cell carcinomas at invasive sites showed clear reduct ion of Cx26 and Cx43. In squamous cell carcinomas metastasized into ly mph nodes, Cx26 was expressed, but few carcinoma cells expressed Cx43, The localization of E-cadherin on the plasma membrane between cancer cells was maintained even at invasive and metastatic sites. Our data s uggest that quantitative and qualitative changes in connexin expressio n are associated with tumor progression, including the loss of differe ntiation, and invasion and metastasis, during multistage mouse skin ca rcinogenesis.