Budunova I V, Carbajal S, Slaga T J
University of Texas M.D. Anderson Cancer Center, Science Park Research Division, Smithville 78957, USA.
Carcinogenesis. 1995 Nov;16(11):2717-24. doi: 10.1093/carcin/16.11.2717.
The loss or alteration of gap junctional intercellular communication (GJIC) has long been proposed to play an important role in the process of carcinogenesis. In this study we examined the expression of three gap junction proteins, connexins (Cx)26, 43 and 31.1, in mouse hyperplastic skin, papillomas and squamous cell carcinomas (SCC). Tumors were induced in SENCAR mice by either of two initiation/promotion protocols: 7,12-dimethylbenz-[a] anthracene (DMBA)/12-O-tetradecanoyl-phorbol-13-acetate (TPA) or DMBA/benzoyl-peroxide (BzPo). Keratinocytes in adult mouse skin expressed Cx31.1 and Cx43 but did not express Cx26. Skin hyperplasia induced by one topical application of TPA was accompanied by hyperexpression of both Cx26 and Cx43. In addition, TPA significantly inhibited the expression of Cx31.1. After repetitive application. Connexin 26 and Cx43 were hyperexpressed in most of the papillomas studied (20-40 weeks after initiation). However, in some late papillomas, immunostaining revealed a focal loss of Cx26. Immunostaining of mouse skin SCC revealed decreased Cx43 and Cx26 levels in 65% and 85% of cases respectively. The high levels of Cx26 and Cx43 mRNA in most of the SCC did not correlate with the decreased abundance or disappearance of Cx26 and Cx43 immunoreactive spots from tumor plasma membranes. Thus, the expression of these two connexins in SCC was impaired at the post-translation level. Cx31.1 expression was strongly inhibited during all stages of carcinogenesis. Taken together, our results suggest that three different connexin genes are differentially regulated during mouse skin carcinogenesis and the decrease of connexin expression may be an important marker of skin tumor expression.
长期以来，人们一直认为间隙连接细胞间通讯（GJIC）的丧失或改变在致癌过程中起重要作用。在本研究中，我们检测了三种间隙连接蛋白，即连接蛋白（Cx）26、43和31.1在小鼠增生性皮肤、乳头状瘤和鳞状细胞癌（SCC）中的表达。通过两种启动/促进方案之一在SENCAR小鼠中诱导肿瘤：7,12-二甲基苯并[a]蒽（DMBA）/12-O-十四烷酰佛波醇-13-乙酸酯（TPA）或DMBA/过氧化苯甲酰（BzPo）。成年小鼠皮肤中的角质形成细胞表达Cx31.1和Cx43，但不表达Cx26。单次局部应用TPA诱导的皮肤增生伴随着Cx26和Cx43的过度表达。此外，TPA显著抑制Cx31.1的表达。重复应用后。在大多数研究的乳头状瘤中（启动后20-40周），连接蛋白26和Cx43过度表达。然而，在一些晚期乳头状瘤中，免疫染色显示Cx26局灶性缺失。小鼠皮肤SCC的免疫染色显示，分别有65%和85%的病例中Cx43和Cx26水平降低。大多数SCC中Cx26和Cx43 mRNA的高水平与肿瘤质膜上Cx26和Cx43免疫反应性斑点的丰度降低或消失无关。因此，这两种连接蛋白在SCC中的表达在翻译后水平受到损害。在致癌的所有阶段，Cx31.1的表达均受到强烈抑制。综上所述，我们的结果表明，在小鼠皮肤致癌过程中三种不同的连接蛋白基因受到不同的调节，连接蛋白表达的降低可能是皮肤肿瘤发生的一个重要标志。
