|A selective aryl hydrocarbon receptor modulator 3,3'-Diindolylmethane inhibits gastric cancer cell growth. |
Yin, XF; Chen, J; Mao, W; Wang, YH; Chen, MH
Journal of experimental & clinical cancer research : CR
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor associated with gastric carcinogenesis. 3,3'-Diindolylmethane (DIM) is a relatively non-toxic selective AhR modulator. This study was to detect the effects of DIM on gastric cancer cell growth.Gastric cancer cell SGC7901 was treated with DIM at different concentrations (0,10,20,30,40,50 μmol/L) with or without an AhR antagonist, resveratrol. The expression of AhR and Cytochrome P4501A1 (CYP1A1), a classic target gene of AhR pathway, were detected by RT-PCR and Western blot; cell viability was measured by MTT assay, and the changes in cell cycle and apoptosis were analyzed by flow cytometry.RT-PCR and western-blot showed that with the increase of the concentration of DIM, AhR protein gradually decreased and CYP1A1 expression increased, suggesting that DIM activated the AhR pathway and caused the translocation of AhR from cytoplasm to nucleus. MTT assay indicated that the viability of SGC7901 cells was significantly decreased in a concentration- and time-dependent manner after DIM treatment and this could be partially reversed by resveratrol. Flow cytometry analysis showed that DIM arrested cell cycle in G1 phase and induced cell apoptosis.Selective aryl hydrocarbon receptor modulator 3,3'-Diindolylmethane inhibits SGC7901 cell proliferation by inducing apoptosis and delaying cell cycle progression. AhR may be a potential therapeutic target for gastric cancer treatment.
|Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9. |
Peng, TL; Chen, J; Mao, W; Song, X; Chen, MH
BMC cell biology
Abberant aryl hydrocarbon receptor (AhR) expression and AhR pathway activation are involved in gastric carcinogenesis. However, the relationship between AhR pathway activation and gastric cancer progression is still unclear. In present study, we used 2,3,7,8-tetrachlorodibenzo-para-dioxin (TCDD), a classic and most potent ligand of AhR, to activate AhR pathway and investigated the effect of AhR pathway activation on human gastric cancer AGS cell invasion and explored the corresponding mechanism.To determine whether AhR pathway can be activated in AGS cells, we examined the expression of CYP1A1, a classic target gene of AhR pathway, following TCDD exposure. RT-PCR and western blot analysis showed that both CYP1A1 mRNA and protein expression were increased in a dose-dependent manner following TCDD treatment and AhR antagonist resveratrol (RSV) could reverse this TCDD-induced CYP1A1 expression. To determine whether TCDD treatment of AGS cells results in an induction of MMP-9 expression, we detected MMP-9 mRNA using RT-PCR and detected MMP-9 enzymatic activity using gelatin zymography. The results showed that both MMP-9 mRNA expression and enzymatic activity were gradually increased with the concentration increase of TCDD in media and these changes could be reversed by RSV treatment in a dose-dependent manner. To examine whether AhR activation-induced MMP-9 expression and activity in AGS cells results in increased migration and invasion, we performed wound healing migration assay and transwell migration and invasion assay. After TCDD treatment, the migration distance and the migration and invasion abilities of AGS cells were increased with a dose-dependent manner. To demonstrate AhR activation-induced MMP-9 expression is mediated by c-Jun, siRNA transfection was performed to silence c-Jun mRNA in AGS cells. The results showed that MMP-9 mRNA expression and activity in untreated control AGS cells were very weak; After TCDD (10 nmol/L) treatment, MMP-9 mRNA expression and activity were significant increased; This TCDD-induced MMP-9 expression and activity increase could be abolished by c-Jun siRNA transfection.AhR pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of MMP-9. Our results provide insight into the mechanism and function of the AhR pathway and its impact on gastric cancer progression.Artículo Texto completo
|Elevated expression of CYP1A1 and gamma-SYNUCLEIN in human ectopic (ovarian) endometriosis compared with eutopic endometrium. |
Singh, MN; Stringfellow, HF; Taylor, SE; Ashton, KM; Ahmad, M; Abdo, KR; El-Agnaf, OM; Martin-Hirsch, PL; Martin, FL
Molecular human reproduction
Endometriosis is a debilitating disease in which apoptotic, genetic, immunological, angiogenic and environmental factors have been implicated. Endocrine-disrupting agents (e.g. dioxins) might be involved. Dioxins, via the arylhydrocarbon receptor (AhR), induce estrogen-metabolizing enzymes CYP1A1 and CYP1B1. Elevated expression of gamma-SYNUCLEIN (gamma-SYN) has been associated with hormone-related conditions. Tissue sets consisting of eutopic and ectopic (ovarian) endometrium from patients with stage 3 or 4 endometriosis were obtained. Following RNA extraction and reverse transcription, quantitative real-time reverse transcriptase-polymerase chain reaction was performed for anti-apoptotic B-cell leukaemia/lymphoma 2 (BCL-2), CYP1A1, CYP1B1, estrogen receptor (ER)alpha, ER beta and gamma-SYN. Immunohistochemical analyses for gamma-syn, ER alpha, ER beta and CYP1A1 were also conducted. A 3-9-fold increase in intra-individual expression of CYP1A1 in ectopic (ovarian) endometrium compared with eutopic tissue was observed; immunohistochemical analyses pointed to CYP1A1 being localized to the glandular epithelium. This intra-individual expression profile was not observed for CYP1B1 or BCL-2. However, a 5-53-fold intra-individual increase in gamma-SYN expression was also demonstrated in six of nine tissue sets (a further two showed an increase that was not considered significant) when comparing ectopic to eutopic endometrium; gamma-syn positivity was associated with endothelial cells. An elevation in ER beta was also noted when comparing ectopic to eutopic endometrium; with regard to ER alpha, this was inconsistent. These results suggest an up-regulation of dioxin-inducible CYP1A1 and gamma-SYN occurs in endometriosis. Whether gamma-syn may be a novel diagnostic marker for endometriosis remains to be ascertained.
|Expression of xenobiotic-metabolizing cytochrome P450 forms in human full-term placenta. |
Hakkola, J, et al.
Biochem. Pharmacol., 51: 403-11 (1996)