Overexpression of ERα inhibits proliferation and invasion of MKN28 gastric cancer cells by suppressing β-catenin

Zhou,Jichun; Teng,Rongyue; Xu,Chaoyang; Wang,Qinchuan; Guo,Jufeng; Xu,Chenpu; Li,Ziduo; Xie,Shuduo; Shen,Jianguo; Wang,Linbo

doi:10.3892/or.2013.2610

Overexpression of ERα inhibits proliferation and invasion of MKN28 gastric cancer cells by suppressing β-catenin

Authors:
- Jichun Zhou
- Rongyue Teng
- Chaoyang Xu
- Qinchuan Wang
- Jufeng Guo
- Chenpu Xu
- Ziduo Li
- Shuduo Xie
- Jianguo Shen
- Linbo Wang
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Affiliations: Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China, Department of Breast and Thyroid Surgery, Shaoxing People's Hospital, The First Affiliated Hospital of Shaoxing Liberal Art College, Shaoxing, Zhejiang 312000, P.R. China
Published online on: July 9, 2013 https://doi.org/10.3892/or.2013.2610
Pages: 1622-1630

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Abstract

The relationship between estrogen receptor (ER)α and patient prognosis has been identified in gastric cancer; however, the definite role of ERα in gastric cancer remains to be fully elucidated. The aim of the present in vitro study was to investigate the impact of ERα on cell proliferation, migration and invasion in gastric cancer cell lines. We investigated the biological effect of ERα overexpression on gastric carcinoma cells. An MKN28 gastric cancer cell line stably overexpressing ERα was established. The effect of ERα overexpression on cell growth was assessed by evaluating cell survival, colony formation, cell cycle progression and apoptosis. Cell migration and invasion were detected by Transwell migration/invasion assays. The protein levels of several potentially involved genes were determined by western blotting to elucidate the underlying molecular mechanisms. The Student's t-test was used to determine the statistical differences between various experimental and control groups, and one-way ANOVA test was used to determine the difference between three or more groups. The results showed that ERα overexpression significantly inhibited cell growth and proliferation, blocked cell entry into the G1/G0 phase and promoted cell apoptosis. In addition, ERα reduced the motility and invasion of gastric cancer cells. These phenotypes may partly be explained by a decrease in β-catenin expression caused by ERα overexpression. ERα overexpression effectively inhibited cell growth and cancer progression by suppressing β-catenin in gastric cancer, identifying ERα as a promising target with therapeutic potential for development of new approaches to treat gastric cancer.

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1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
2	Kamangar F, Dores GM and Anderson WF: Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 24:2137–2150. 2006. View Article : Google Scholar
3	Clarke M, Collins R, Davies C, et al: Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Lancet. 351:1451–1467. 1998. View Article : Google Scholar : PubMed/NCBI
4	Abe O, Abe R, Enomoto K, et al: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Lancet. 365:1687–1717. 2005.PubMed/NCBI
5	Tokunaga A, Nishi K, Matsukura N, et al: Estrogen and progesterone receptors in gastric cancer. Cancer. 57:1376–1379. 1986. View Article : Google Scholar : PubMed/NCBI
6	Bianchi F, Hu J, Pelosi G, et al: Lung cancers detected by screening with spiral computed tomography have a malignant phenotype when analyzed by cDNA microarray. Clin Cancer Res. 10:6023–6028. 2004. View Article : Google Scholar : PubMed/NCBI
7	Zhang N, Zhang J, Shuai L, et al: Krüppel-like factor 4 negatively regulates β-catenin expression and inhibits the proliferation, invasion and metastasis of gastric cancer. Int J Oncol. 40:2038–2048. 2012.
8	Kouzmenko AP, Takeyama K, Ito S, et al: Wnt/β-catenin and estrogen signaling converge in vivo. J Biol Chem. 279:40255–40258. 2004.
9	Crew KD and Neugut AI: Epidemiology of gastric cancer. World J Gastroenterol. 12:354–362. 2006.
10	Brenner H, Rothenbacher D and Arndt V: Epidemiology of stomach cancer. Methods Mol Biol. 472:467–477. 2009. View Article : Google Scholar
11	Parkin D, Whelan S, Ferlay J, Teppo L and Thomas D: Cancer incidence in five continents. Volume VIII. IARC Sci Publ. 155:1–781. 2002.PubMed/NCBI
12	Chandanos E and Lagergren J: Oestrogen and the enigmatic male predominance of gastric cancer. Eur J Cancer. 44:2397–2403. 2008. View Article : Google Scholar : PubMed/NCBI
13	La Vecchia C, D’Avanzo B, Franceschi S, Negri E, Parazzini F and Decarli A: Menstrual and reproductive factors and gastric-cancer risk in women. Int J Cancer. 59:761–764. 1994.
14	Frise S, Kreiger N, Gallinger S, Tomlinson G and Cotterchio M: Menstrual and reproductive risk factors and risk for gastric adenocarcinoma in women: findings from the Canadian National Enhanced Cancer Surveillance system. Ann Epidemiol. 16:908–916. 2006. View Article : Google Scholar : PubMed/NCBI
15	Lindblad M, Ye W, Rubio C and Lagergren J: Estrogen and risk of gastric cancer: a protective effect in a nationwide cohort study of patients with prostate cancer in Sweden. Cancer Epidemiol Biomarkers Prev. 13:2203–2207. 2004.PubMed/NCBI
16	Freedman ND, Chow WH, Gao YT, et al: Menstrual and reproductive factors and gastric cancer risk in a large prospective study of women. Gut. 56:1671–1677. 2007. View Article : Google Scholar : PubMed/NCBI
17	Green J, Czanner G, Reeves G, et al: Menopausal hormone therapy and risk of gastrointestinal cancer: nested case-control study within a prospective cohort, and meta-analysis. Int J Cancer. 130:2387–2396. 2012. View Article : Google Scholar : PubMed/NCBI
18	Lindblad M, García Rodríguez LA, Chandanos E and Lagergren J: Hormone replacement therapy and risks of oesophageal and gastric adenocarcinomas. Br J Cancer. 94:136–141. 2006. View Article : Google Scholar : PubMed/NCBI
19	Chandanos E, Lindblad M, Jia C, Rubio CA, Ye W and Lagergren J: Tamoxifen exposure and risk of oesophageal and gastric adenocarcinoma: a population-based cohort study of breast cancer patients in Sweden. Br J Cancer. 95:118–122. 2006. View Article : Google Scholar : PubMed/NCBI
20	Chandanos E, Lindblad M, Rubio CA, et al: Tamoxifen exposure in relation to gastric adenocarcinoma development. Eur J Cancer. 44:1007–1014. 2008. View Article : Google Scholar : PubMed/NCBI
21	Harrison JD, Watson S and Morris DL: The effect of sex hormones and tamoxifen on the growth of human gastric and colorectal cancer cell lines. Cancer. 63:2148–2151. 1989. View Article : Google Scholar : PubMed/NCBI
22	Takano N, Iizuka N, Hazama S, Yoshino S, Tangoku A and Oka M: Expression of estrogen receptor-α and -β mRNAs in human gastric cancer. Cancer Lett. 176:129–135. 2002.
23	Furukawa H, Iwanaga T, Koyama H and Taniguchi H: Effect of sex hormones on carcinogenesis in the stomachs of rats. Cancer Res. 42:5181–5182. 1982.PubMed/NCBI
24	Campbell-Thompson M, Lauwers GY, Reyher KK, Cromwell J and Shiverick KT: 17β-estradiol modulates gastroduodenal preneoplastic alterations in rats exposed to the carcinogen N-methyl-N′-nitro-nitrosoguanidine. Endocrinology. 140:4886–4894. 1999.
25	Furukawa H, Iwanaga T, Hiratsuka M, et al: Suppressive effect of sex hormones on spreading of stomach cancer. Gan To Kagaku Ryoho. 16:3691–3695. 1989.(In Japanese).
26	Furukawa H, Iwanaga T, Koyama H and Taniguchi H: Effect of sex hormones on the experimental induction of cancer in rat stomach - a preliminary study. Digestion. 23:151–155. 1982. View Article : Google Scholar : PubMed/NCBI
27	Greene GL, Gilna P, Waterfield M, Baker A, Hort Y and Shine J: Sequence and expression of human estrogen receptor complementary DNA. Science. 231:1150–1154. 1986. View Article : Google Scholar : PubMed/NCBI
28	Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S and Gustafsson JA: Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA. 93:5925–5930. 1996. View Article : Google Scholar : PubMed/NCBI
29	Green S, Walter P, Kumar V, et al: Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature. 320:134–139. 1986. View Article : Google Scholar : PubMed/NCBI
30	Wu CW, Chang YF, Yeh TH, et al: Steroid hormone receptors in three human gastric cancer cell lines. Dig Dis Sci. 39:2689–2694. 1994. View Article : Google Scholar : PubMed/NCBI
31	Karat D, Brotherick I, Shenton BK, Scott D, Raimes SA and Griffin SM: Expression of oestrogen and progesterone receptors in gastric cancer: a flow cytometric study. Br J Cancer. 80:1271–1274. 1999. View Article : Google Scholar : PubMed/NCBI
32	Chandanos E, Rubio CA, Lindblad M, et al: Endogenous estrogen exposure in relation to distribution of histological type and estrogen receptors in gastric adenocarcinoma. Gastric Cancer. 11:168–174. 2008. View Article : Google Scholar : PubMed/NCBI
33	Matsui M, Kojima O, Uehara Y and Takahashi T: Characterization of estrogen receptor in human gastric cancer. Cancer. 68:305–308. 1991. View Article : Google Scholar : PubMed/NCBI
34	Wu CW, Lui WY, P’eng FK and Chi CW: Hormonal therapy for stomach cancer. Med Hypotheses. 39:137–139. 1992. View Article : Google Scholar : PubMed/NCBI
35	Machado JC, Carneiro F, Gärtner F, Ribeiro P and Sobrinho-Simões M: Female sex hormone receptors are not involved in gastric carcinogenesis. A biochemical and immunohistochemical study. Eur J Cancer Prev. 3:31–37. 1994. View Article : Google Scholar : PubMed/NCBI
36	Singh S, Poulsom R, Wright NA, Sheppard MC and Langman MJ: Differential expression of oestrogen receptor and oestrogen inducible genes in gastric mucosa and cancer. Gut. 40:516–520. 1997. View Article : Google Scholar : PubMed/NCBI
37	Xu CY, Guo JL, Jiang ZN, et al: Prognostic role of estrogen receptor α and estrogen receptor β in gastric cancer. Ann Surg Oncol. 17:2503–2509. 2010.
38	Gan L, He J, Zhang X, et al: Expression profile and prognostic role of sex hormone receptors in gastric cancer. BMC Cancer. 12:5662012. View Article : Google Scholar : PubMed/NCBI
39	Kitaoka H: Sex hormone dependency and endocrine therapy in diffuse carcinoma of the stomach]. Gan To Kagaku Ryoho. 10:2453–2460. 1983.(In Japanese).
40	Matsui M, Kojima O, Kawakami S, Uehara Y and Takahashi T: The prognosis of patients with gastric cancer possessing sex hormone receptors. Surg Today. 22:421–425. 1992. View Article : Google Scholar : PubMed/NCBI
41	Zhao XH, Gu SZ, Liu SX and Pan BR: Expression of estrogen receptor and estrogen receptor messenger RNA in gastric carcinoma tissues. World J Gastroenterol. 9:665–669. 2003.PubMed/NCBI
42	Yokozaki H, Takekura N, Takanashi A, Tabuchi J, Haruta R and Tahara E: Estrogen receptors in gastric adenocarcinoma: a retrospective immunohistochemical analysis. Virchows Arch A Pathol Anat Histopathol. 413:297–302. 1988. View Article : Google Scholar : PubMed/NCBI
43	Wang M, Pan JY, Song GR, Chen HB, An LJ and Qu SX: Altered expression of estrogen receptor α and β in advanced gastric adenocarcinoma: correlation with prothymosin α and clinicopathological parameters. Eur J Surg Oncol. 33:195–201. 2007.
44	Kitaoka H: Chemo-endocrine therapy of diffuse carcinoma of the stomach and its clinical evaluation. Gan No Rinsho. 31:1189–1194. 1985.(In Japanese).
45	Koullias GJ, Pratsinis CI, Korkolis DP, et al: Brief tamoxifen pretreatment enhances the chemosensitivity of gastric carcinoma cells to 5-fluorouracil in vitro. Anticancer Res. 23:1575–1580. 2003.PubMed/NCBI
46	Matsuyama S, Ohkura Y, Eguchi H, et al: Estrogen receptor β is expressed in human stomach adenocarcinoma. J Cancer Res Clin Oncol. 128:319–324. 2002.
47	Ryu WS, Kim JH, Jang YJ, et al: Expression of estrogen receptors in gastric cancer and their clinical significance. J Surg Oncol. 106:456–461. 2012. View Article : Google Scholar : PubMed/NCBI
48	Ozawa M, Ringwald M and Kemler R: Uvomorulin-catenin complex formation is regulated by a specific domain in the cytoplasmic region of the cell adhesion molecule. Proc Nat Acad Sci USA. 87:4246–4250. 1990. View Article : Google Scholar : PubMed/NCBI
49	Conacci-Sorrell M, Simcha I, Ben-Yedidia T, Blechman J, Savagner P and Ben-Ze’ev A: Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of β-catenin signaling, Slug, and MAPK. J Cell Biol. 163:847–857. 2003.PubMed/NCBI
50	Logan CY and Nusse R: The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 20:781–810. 2004. View Article : Google Scholar : PubMed/NCBI
51	Kanwar SS, Yu Y, Nautiyal J, Patel BB and Majumdar AP: The Wnt/β-catenin pathway regulates growth and maintenance of colonospheres. Mol Cancer. 9:2122010.
52	Hervieu V, Lepinasse F, Gouysse G, et al: Expression of β-catenin in gastroenteropancreatic endocrine tumours: a study of 229 cases. J Clin Pathol. 59:1300–1304. 2006.
53	Lin SY, Xia W, Wang JC, et al: β-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression. Proc Nat Acad Sci USA. 97:4262–4266. 2000.
54	Wong SC, Lo ES, Lee KC, Chan JK and Hsiao WL: Prognostic and diagnostic significance of β-catenin nuclear immunostaining in colorectal cancer. Clin Cancer Res. 10:1401–1408. 2004.