Abstract
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)/12Otetradecanoyl-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 hyper-expression of both Cx26 and Cx43. In addition, TPA significantly inhibited the expression of Cx31.1. After repetitive application of TPA for 3 weeks to initiated mouse skin, a similar Cx profile was found to that after a single TPA application. Connexin 26 and Cx43 were hyper-expressed 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 progression.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2717-2724 |
| Number of pages | 8 |
| Journal | Carcinogenesis |
| Volume | 16 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1995 |
Funding
We gratefully acknowledge Drs D.L.Paul and J.A.Goliger (Department of Neurobiology, Harvard Medical School, Boston, MA) for their generous gift of Cx26, Cx31.1 and Cx43 cDNAs. We are also indebted to them for providing the polyclonal antibodies to the synthetic peptide corresponding to amino acids 108-122 in Cx26 and to the affinity purified fusion protein containing amino acids 202-271 of Cx31.l. A rabbit polyclonal anti-Cx43 antibody was kindly provided by Dr VA.Krutovskikh (International Agency on Cancer Research, Lyon, France). The authors thank Dr I.B.Gimenez-Conti (Department of Carcinogenesis, the University of Texas M.D.Anderson Cancer Center) for help in the morphological diagnosis of skin tumors and Ms T.McAbee for preparation of histological slides and frozen sections. Supported by National Cancer Institute grants CA-57796 and CA-16672.
ASJC Scopus subject areas
- Cancer Research
