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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gap junctional intercellular communication (GJIC) and the expression of gap junction proteins (connexins) may be involved in growth regulation and neoplastic transformation. The mechanisms of connexin gene regulation in normal and neoplastic tissues are poorly understood. In this study, the glucocorticoids, dexamethasone and hydrocortisone, enhanced fluorescent dye-coupling in primary cultured rat hepatocytes and MH1C1 rat hepatoma cells. Other types of steroids (beta-estradiol, testosterone, aldosterone and progesterone) had no effect. Northern blot, Western blot, nuclear run-on and immunohistochemical analyses showed that glucocorticoids enhanced the expression of connexin32 in these cells in a dose- and time-dependent fashion. Connexin26 expression was also enhanced slightly by dexamethasone in hepatocytes, but not MH1C1 cells. Connexin43 expression in these cells was not affected by steroids. In WB-F344 rat liver epithelial cells, which were highly coupled and expressed high levels of connexin43 and no detectable connexin32 or connexin26, dexamethasone had no effect on coupling or connexin expression. These results indicate that dye-coupling and the expression of connexin32 and connexin26, but not connexin43, were upregulated by glucocorticoids in a cell-specific manner. These effects on GJIC and connexin expression may be involved in the induction of hepatic differentiation and inhibition of growth.
Carcinogenesis 1994 Sep
PMID:Enhancement of liver cell gap junction protein expression by glucocorticoids. 752 79

The mouse pneumotoxicant and lung and liver tumor promoter butylated hydroxytoluene (BHT) was examined for its effects on gap junctional intercellular communication (GJIC) in mouse lung epithelial (C10) and rat liver epithelial (WB-F344) cell lines. GJIC, as measured by fluorescent dye microinjection, was inhibited in both types of cells by BHT in dose- and time-dependent fashions. Inhibition was detected in WB-F344 cells at BHT concentrations > or = 62.5 microM and in C10 cells at concentrations > or = 150 microM after 4 h treatment. Inhibition occurred within 15-30 min and was reversed by removing BHT from the culture medium. The highly toxic BHT metabolite 6-t-butyl-2-(hydroxy-t-butyl)-4-methylphenol (BHTOH) and the non-toxic BHT metabolite, 2,6-di-t-butyl-4-hydroxymethylphenol (BHTBzOH) were also tested. In both cell lines BHTOH was a more potent inhibitor of GJIC than BHT, whereas BHTBzOH was ineffective. The mechanisms of inhibition of GJIC by BHT were also examined. The initial rapid inhibition detected within 15-30 min may have been due to gap junction channel closure or blockage, since no changes in gap junction number, connexin (Cx) 43 levels or Cx43 phosphorylation were observed. By 2-4 h, however, gap junctions were internalized into the cytoplasm, the number of immunodetectable plasma membrane gap junctions was reduced and phosphorylated Cx43-P2 was decreased. Treatment of the cells for 24 h with 12-O-tetradecanoylphorbol-13-acetate (TPA) prevented inhibition of GJIC by TPA, but not by BHT. Western blot analyses of TPA-treated WB-F344 or C10 cells revealed the presence of a hyperphosphorylated form of Cx43 (Cx43-P3) and no reduction in Cx43-P2, in contrast to BHT-treated cells. These data suggest that BHT and TPA inhibit lung and liver epithelial cell GJIC through distinct mechanisms.
Carcinogenesis 1995 Oct
PMID:Down-regulation by butylated hydroxytoluene of the number and function of gap junctions in epithelial cell lines derived from mouse lung and rat liver. 758 69

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.
Carcinogenesis 1995 Nov
PMID:The expression of gap junctional proteins during different stages of mouse skin carcinogenesis. 758 91

To elucidate what changes in the expression of gap junction proteins (connexins) occur at what stages during multistage mouse skin carcinogenesis in vivo, we immunohistochemically and morphometrically analyzed the expression of connexin 26 (Cx26) and connexin 43 (Cx43) in papillomas, well-, moderately- and poorly-differentiated squamous cell carcinomas, as well as in squamous cell carcinomas at invasion sites and those metastasized into lymph nodes in female CD-1 mice as a result of treatment with dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. In papillomas, no clear reduction of the two connexins was observed; however, Cx26 and Cx43 were frequently co-localized in the same gap junction plaques, whereas the two kinds of Cxs were differentially expressed in normal and surrounding non-tumorous epidermis. In squamous cell carcinomas, the expression of both Cx26 and Cx43 significantly decreased compared with surrounding non-tumorous epidermis and papillomas. The Western blot analysis confirmed that both Cx26 and Cx43 proteins were reduced in squamous cell carcinomas compared with papillomas. Furthermore, the expression of Cx26 was reduced as cancer cells became morphologically less differentiated, while that of Cx43 did not change. Squamous cell carcinomas at invasive sites showed clear reduction of Cx26 and Cx43. In squamous cell carcinomas metastasized into lymph 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 suggest that quantitative and qualitative changes in connexin expression are associated with tumor progression, including the loss of differentiation, and invasion and metastasis, during multistage mouse skin carcinogenesis.
Carcinogenesis 1995 Jun
PMID:Aberrant expression of gap junction proteins (connexins) is associated with tumor progression during multistage mouse skin carcinogenesis in vivo. 778 45

The effects of in vivo exposure to DDT on hepatic gap junctional intercellular communication (GJIC) and connexin gene/protein expression in Sprague-Dawley rats were examined by in vivo/in vitro dye-transfer assay, immunohistochemical staining, and by Western and Northern blot analyses. In the dose-response study, three dose levels of DDT (5, 25 and 50 mg/kg/day) were administered orally to rats once a day for 2 weeks. The average size of the dye spread after injection of Lucifer Yellow and the area of Cx32 spots per hepatocyte decreased in a dose-dependent manner, but there was no effect on the number of Cx32 spots per hepatocyte. In the time-course study, DDT (50 mg/kg/day) was administered orally once a day for up to 6 weeks. Hepatic GJIC decreased at week 1 but recovered at week 6. The average area of Cx32 spots per hepatocyte gradually decreased at weeks 2 and 4, and remained at the same level at week 6, correlating with the decreased Cx32 protein level in plasma membranes. The average area of Cx26 spots per hepatocyte in the peripheral zones clearly decreased at week 1, but quickly recovered at week 2 and increased at week 6; however, no clear change of the Cx26 protein level in plasma membranes was observed. No changes of Cx32 and Cx26 mRNA levels were observed in DDT groups. These results suggest that DDT, a liver tumor-promoting agent, inhibits hepatic GJIC in vivo dose-dependently in rats and that aberrant Cx32 and Cx26 protein expression and/or localization may be responsible for this effect.
Carcinogenesis 1994 Mar
PMID:Effect of DDT on hepatic gap junctional intercellular communication in rats. 790 10

We have studied the gap junctional intercellular communication (GJIC) of immortalized and tumourigenic human keratinocyte cell lines and of a spontaneously immortalized non-tumourigenic and a highly differentiating keratinocyte cell line (HaCaT) as the control. In homologous cultures, the GJIC capacity of five squamous cell carcinoma-derived cell lines was 1-27% that of the HaCaT cells. Ha-ras-transfected HaCaT cells with tumourigenic potential and an SV40 DNA-immortalized cell line had markedly reduced GJIC capacities. Northern analysis and immunohistochemistry showed that connexin (Cx) 43 is the major gap junction protein expressed in the communicating cells. They do not express Cx 26 or 32. The low or absent communication observed in certain cell lines was due in some to a lack of Cx 43 gene expression, but in others to aberrant localization of the gap junction protein. GJIC of these cell lines, as well as that of primary normal human epidermal keratinocytes, was susceptible to 12-O-tetradecanoylphorbol-13-acetate-mediated inhibition. Moreover, GJIC of HaCaT cells and their tumourigenic derivatives is Ca(2+)-dependent. These results, when compared with those previously obtained for mouse keratinocyte cell lines, reveal that GJIC of human keratinocytes was correlated to the degree of differentiation and is controlled in a similar way to that of murine keratinocytes. Aberrant GJIC seems to be a common feature of human and murine skin carcinogenesis.
Carcinogenesis 1994 Sep
PMID:Expression and function of connexin in normal and transformed human keratinocytes in culture. 792 78

Many reports have suggested that gap junctional intercellular communication or gap junction proteins (connexins) could have tumor suppression characteristics. We investigated gap junctional intercellular communication capacity and connexin 26, 32 and 43 mRNA expression in four rat bladder cell lines and the results were compared to their tumorigenicity. We also examined connexin expression in rat bladder carcinomas induced by 3,2'-dimethyl-4-aminobiphenyl or N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) and in normal bladders. There was clear tendency that cell lines with greater communication had stronger tumorigenicity and more expression of connexin 26 or 43. We could not detect connexin 32 in these cell lines. In normal bladder tissue, connexin 43 expression was barely detectable and there was no detectable connexin 26. However, in rat bladder carcinomas, especially the EHBN-induced carcinomas, abundant expression of both connexins was observed. These results indicate that increased gap junctional intercellular communication capacity or increased connexin(s) expression may give a growth advantage in rat bladder carcinogenesis.
Carcinogenesis 1994 Oct
PMID:Increased gap junctional intercellular communication capacity and connexin 43 and 26 expression in rat bladder carcinogenesis. 795 49

Polychlorinated biphenyls (PCBs) are industrial chemicals which are highly persistent and widely distributed in the environment. We have previously shown that 3,4,5,3',4'-pentachlorobiphenyl (PCB 126) is a potent tumour promoter in two separate 20 week initiation-promotion studies. In the present study, rat livers from these two studies were further investigated for connexin expression. The results demonstrated that treatment with PCB 126 caused a decrease in the amount of the two major liver connexins, cx 26 and cx 32, in livers of treated animals. This reduction was also prominent after treatment at low doses, although gamma-glutamyl transpeptidase-positive foci had not developed in these livers. The quantity of cx 26 and cx 32 in immunostained liver sections was determined using a computerized fluorescence image analyzer. Western blot analysis of liver extracts confirmed these results. No changes in the RNA levels in the treated rats were seen, suggesting that the down-regulation of cx 26 and cx 32 is post-transcriptional.
Carcinogenesis 1994 Nov
PMID:Alteration in expression of gap junction proteins in rat liver after treatment with the tumour promoter 3,4,5,3',4'-pentachlorobiphenyl. 795 88

Gap junctional intercellular communication (GJIC) is often modulated by chemical carcinogens and during carcinogenesis, in part, through changes in gap junction mRNA levels. However, the mechanisms by which gap junction mRNA levels are altered in either normal or cancer cells are largely unknown. Since glucocorticoids are potent modulators of gene expression and stability, we have investigated the effects of these hormones on GJIC and gap junction mRNA expression in rat hepatocytes cultured in three different media. Addition of dexamethasone to cultures of rat hepatocytes resulted in a maintenance of GJIC and both major liver gap junctional mRNAs, connexin (Cx)26 and Cx32, at levels above those in hepatocytes cultured in glucocorticoid-free media. In addition, hepatocytes cultured without dexamethasone for 24 h could be induced to communicate and increase Cx mRNA levels by the addition of dexamethasone to their medium. These media-independent changes in GJIC and gap junction mRNA levels by dexamethasone warrant further investigations into their mechanisms of action and the potential therapeutic value of glucocorticoids in the treatment of cancer.
Carcinogenesis 1994 Aug
PMID:Comparison of glucocorticoid-mediated changes in the expression and function of rat hepatocyte gap junctional proteins. 805 59

12-O-Tetradecanoylphorbol-13-acetate (TPA), trans-retinoic acid (RA) and DDT inhibit gap junctional intercellular communication in Syrian hamster embryo (SHE) cells. The inhibition is rapid and takes place within minutes. Northern blot analysis shows that SHE cells express connexin 43 and that exposure to these compounds for up to 20 h has no effect on connexin 43 mRNA level. Immune cytochemistry shows that the connexon structures in SHE cells are scattered over the cell, and not confined to the cell-cell boundaries as is the case in the rat liver epithelial cell line IAR20. RA and TPA induce the disappearance of the connexon structures in parallel to the induced inhibition of communication in SHE cells. The disappearance of the connexon spots takes place with no apparent effect on the cellular content of connexin protein measured by immunoblotting, and is probably caused by disaggregation of the connexon structures rather than disappearance or degradation of the connexin protein. DDT shows little or no apparent effect on connexin immunostaining in SHE cells, indicating a different mechanism of action. In the IAR20 cells, exposure to TPA and RA also results in loss of immunostainable connexon structures while exposure to DDT results in relocalization of the connexons away from the cell-cell borders. Immunoblotting of connexin 43 in SHE cells results in three major bands with apparent mol. wts of 40-50 kDa where the two higher mol. wt bands represent phosphorylated connexin 43 protein. Exposure of the cells to the communication inhibiting compounds results in reduction or loss of the highest mol. wt phosphorylated band, indicating a relation between a specific connexin phosphorylation and aggregation of connexin 43 protein to functional communicating gap junctions. The results suggest the presence of various post-transcriptional control mechanisms in the regulation of connexin function which are vulnerable to exogenous stimuli.
Carcinogenesis 1994 Apr
PMID:Inhibition of gap junctional intercellular communication in Syrian hamster embryo cells by TPA, retinoic acid and DDT. 814 81


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