Downregulation of aryl hydrocarbon receptor expression decreases gastric cancer cell growth and invasion

Yin,Xiao-Fei; Chen,Jie; Mao,Wei; Wang,Yu-Hong; Chen,Min-Hu

doi:10.3892/or.2013.2410

Downregulation of aryl hydrocarbon receptor expression decreases gastric cancer cell growth and invasion

Authors:
- Xiao-Fei Yin
- Jie Chen
- Wei Mao
- Yu-Hong Wang
- Min-Hu Chen
View Affiliations

Affiliations: Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: April 22, 2013 https://doi.org/10.3892/or.2013.2410
Pages: 364-370

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor associated with tumor initiation and progression. AhR expression is significantly increased in gastric cancer tissues and gastric cancer cell lines; however, the relationship between AhR and gastric cancer is still unclear. In the present study, we explored the effects of the inhibition of AhR expression by RNA interference on the biological behavior of gastric cancer cells (MKN45 and SGC7901), and elucidated the specific mechanisms of AhR action in the development of gastric cancer. Results showed that small interfering RNA (siRNA) against AhR effectively inhibited the expression of AhR, and decreased the expression of cytochrome P450 (CYP)1A1 and CYP1B1, which are classic target genes of the AhR pathway. Compared to the negative control group, AhR-siRNA-transfected cells showed decreased cellular growth, delayed G1-S cell cycle progression and increased apoptosis rate. Furthermore, inhibition of AhR expression by siRNA in SGC7901 cells led to decreased cell migratory and invasive ability, accompanied by downregulation of expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9. Our results, therefore, suggest that AhR promotes the growth and invasiveness of gastric cancer cells and AhR may serve as a promising therapeutic target for gastric cancer.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar
2	Crew KD and Neugut AI: Epidemiology of gastric cancer. World J Gastroenterol. 12:354–362. 2006.
3	Belpomme D, Irigaray P, Hardell L, Clapp R, Montagnier L, Epstein S and Sasco AJ: The multitude and diversity of environmental carcinogens. Environ Res. 105:414–429. 2007. View Article : Google Scholar : PubMed/NCBI
4	Mandal PK: Dioxin: a review of its environmental effects and its aryl hydrocarbon receptor biology. J Comp Physiol B. 175:221–230. 2005. View Article : Google Scholar : PubMed/NCBI
5	Schwarz M and Appel KE: Carcinogenic risks of dioxin: mechanistic considerations. Regul Toxicol Pharmacol. 43:19–34. 2005. View Article : Google Scholar : PubMed/NCBI
6	Whitelaw M, Pongratz I, Wilhelmsson A, Gustafsson JA and Poellinger L: Ligand-dependent recruitment of the Arnt coregulator determines DNA recognition by the dioxin receptor. Mol Cell Biol. 13:2504–2514. 1993.PubMed/NCBI
7	Rowlands JC and Gustafsson JA: Aryl hydrocarbon receptor-mediated signal transduction. Crit Rev Toxicol. 27:109–134. 1997. View Article : Google Scholar : PubMed/NCBI
8	Gasiewicz TA: Expression and activity of aryl hydrocarbon receptors in development and cancer. Crit Rev Eukaryot Gene Expr. 18:279–321. 2008. View Article : Google Scholar : PubMed/NCBI
9	Puga A, Xia Y and Elferink C: Role of the aryl hydrocarbon receptor in cell cycle regulation. Chem Biol Interact. 141:117–130. 2002. View Article : Google Scholar : PubMed/NCBI
10	Abdelrahim M, Smith R III and Safe S: Aryl hydrocarbon receptor gene silencing with small inhibitory RNA differentially modulates Ah-responsiveness in MCF-7 and HepG2 cancer cells. Mol Pharmacol. 63:1373–1381. 2003. View Article : Google Scholar : PubMed/NCBI
11	Ishida M, Mikami S, Kikuchi E, Kosaka T, Miyajima A, Nakagawa K, Mukai M, Okada Y and Oya M: Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by up-regulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer. Carcinogenesis. 31:287–295. 2010. View Article : Google Scholar : PubMed/NCBI
12	Hsu EL, Yoon D, Choi HH, et al: A proposed mechanism for the protective effect of dioxin against breast cancer. Toxicol Sci. 98:436–444. 2007. View Article : Google Scholar : PubMed/NCBI
13	Peng TL, Chen J, Mao W, Liu X, Tao Y, Chen LZ and Chen MH: Potential therapeutic significance of increased expression of aryl hydrocarbon receptor in human gastric cancer. World J Gastroenterol. 15:1719–1729. 2009. View Article : Google Scholar : PubMed/NCBI
14	Peng TL, Chen J, Mao W, Song X and Chen MH: Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9. BMC Cell Biol. 10:272009. View Article : Google Scholar
15	Nebert DW, Puga A and Vasiliou V: Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction. Ann NY Acad Sci. 685:624–640. 1993.PubMed/NCBI
16	Zheng H, Takahashi H, Murai Y, et al: Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma. Anticancer Res. 26:3579–3583. 2006.PubMed/NCBI
17	Lin P, Chang H, Tsai WT, Wu MH, Liao YS, Chen JT and Su JM: Overexpression of aryl hydrocarbon receptor in human lung carcinomas. Toxicol Pathol. 31:22–30. 2003. View Article : Google Scholar : PubMed/NCBI
18	Kim JH, Kim H, Lee KY, et al: Aryl hydrocarbon receptor gene polymorphisms affect lung cancer risk. Lung Cancer. 56:9–15. 2007. View Article : Google Scholar : PubMed/NCBI
19	Schlezinger JJ, Liu D, Farago M, Seldin DC, Belguise K, Sonenshein GE and Sherr DH: A role for the aryl hydrocarbon receptor in mammary gland tumorigenesis. Biol Chem. 387:1175–1187. 2006. View Article : Google Scholar : PubMed/NCBI
20	Long JR, Egan KM, Dunning L, et al: Population-based case-control study of AhR (aryl hydrocarbon receptor) and CYP1A2 polymorphisms and breast cancer risk. Pharmacogenet Genomics. 16:237–243. 2006. View Article : Google Scholar : PubMed/NCBI
21	Koliopanos A, Kleeff J, Xiao Y, Safe S, Zimmermann A, Büchler MW and Friess H: Increased arylhydrocarbon receptor expression offers a potential therapeutic target for pancreatic cancer. Oncogene. 21:6059–6070. 2002. View Article : Google Scholar
22	Moennikes O, Loeppen S, Buchmann A, Andersson P, Ittrich C, Poellinger L and Schwarz M: A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res. 64:4707–4710. 2004. View Article : Google Scholar : PubMed/NCBI
23	Hillegass JM, Murphy KA, Villano CM and White LA: The impact of aryl hydrocarbon receptor signaling on matrix metabolism: implications for development and disease. Biochem Pharmacol. 387:1159–1173. 2006.PubMed/NCBI
24	Villano CM, Murphy KA, Akintobi A and White LA: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces matrix metalloproteinase (MMP) expression and invasion in A2058 melanoma cells. Toxicol Appl Pharmacol. 210:212–224. 2006.
25	Martinez JM, Afshari CA, Bushel PR, Masuda A, Takahashi T and Walker NJ: Differential toxicogenomic responses to 2,3,7,8-tetrachlorodibenzo-p-dioxin in malignant and nonmalignant human airway epithelial cells. Toxicol Sci. 69:409–423. 2002. View Article : Google Scholar : PubMed/NCBI
26	Haque M, Francis J and Sehgal I: Aryl hydrocarbon exposure induces expression of MMP-9 in human prostate cancer cell lines. Cancer Lett. 225:159–166. 2005. View Article : Google Scholar : PubMed/NCBI
27	Deryugina EI and Quigley JP: Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 25:9–34. 2006. View Article : Google Scholar
28	Sier CF, Kubben FJ, Ganesh S, et al: Tissue levels of matrix metalloproteinases MMP-2 and MMP-9 are related to the overall survival of patients with gastric carcinoma. Br J Cancer. 74:413–417. 1996. View Article : Google Scholar : PubMed/NCBI