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The direct effect of estrogen on cell viability and apoptosis in human gastric cancer cells

Abstract

Epidemiology researches indicated that gastric cancer is a male-predominant disease; both expression level of estrogen and expression pattern of estrogen receptors (ERs) influence its carcinogenesis. But the direct effect of estrogen on gastric cancer cells is still unclear. This study aimed to explore the direct effect of β-estradiol (E2) on gastric cancer cells. SGC7901 and BGC823 were treated with a serial of concentrations of E2. The survival rates of both the cell lines were significantly reduced, and the reduction of viability was due to apoptosis triggered by E2 treatment. Caspase 3 was activated in response to the increasing E2 concentration in both SGC7901 and BGC823. Cleaved Caspase 3 fragments were detected, and the expression levels of Bcl-2 and Bcl-xL were reduced. Apoptosis was further confirmed by flow cytometry. The expression level of PEG10, an androgen receptor target gene, was reduced during E2 treatment. Both ERα and ERβ were expressed in these cell lines, and the result of bioinformatics analysis of gastric cancer from GEO datasets indicated that the expression levels of both ERα and ERβ were significantly higher in noncancerous gastric tissues than in gastric cancer tissues. Our research indicated that estrogen can reduce cell viability and promote apoptosis in gastric cancer cells directly; ERs expression level is associated with gastric cancer. Our research will help to understand the mechanism of gender disparity in gastric cancer.

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References

  1. Bertuccio P, Chatenoud L, Levi F, Praud D, Ferlay J, Negri E, Malvezzi M, La Vecchia C (2009) Recent patterns in gastric cancer: a global overview. Int J Cancer 125(3):666–673. doi:10.1002/ijc.24290

    CAS  PubMed  Google Scholar 

  2. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90

    PubMed  Article  Google Scholar 

  3. Sipponen P, Correa P (2002) Delayed rise in incidence of gastric cancer in females results in unique sex ratio (M/F) pattern: etiologic hypothesis. Gastric Cancer 5(4):213–219. doi:10.1007/s101200200037

    PubMed  Article  Google Scholar 

  4. Chandanos E, Lagergren J (2008) Oestrogen and the enigmatic male predominance of gastric cancer. Eur J Cancer 44(16):2397–2403. doi:10.1016/j.ejca.2008.07.031

    CAS  PubMed  Article  Google Scholar 

  5. Lindblad M, Ye W, Rubio C, Lagergren J (2004) 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(12):2203–2207

    CAS  PubMed  Google Scholar 

  6. Ohtani M, Garcia A, Rogers AB, Ge Z, Taylor NS, Xu S, Watanabe K, Marini RP, Whary MT, Wang TC, Fox JG (2007) Protective role of 17 beta -estradiol against the development of Helicobacter pylori-induced gastric cancer in INS-GAS mice. Carcinogenesis 28(12):2597–2604. doi:10.1093/carcin/bgm150

    CAS  PubMed  Article  Google Scholar 

  7. Ohtani M, Ge Z, Garcia A, Rogers AB, Muthupalani S, Taylor NS, Xu S, Watanabe K, Feng Y, Marini RP, Whary MT, Wang TC, Fox JG (2011) 17 beta-estradiol suppresses Helicobacter pylori-induced gastric pathology in male hypergastrinemic INS-GAS mice. Carcinogenesis 32(8):1244–1250. doi:10.1093/carcin/bgr072

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  8. El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576. doi:10.1053/j.gastro.2007.04.061

    CAS  PubMed  Article  Google Scholar 

  9. Bosch FX, Ribes J, Diaz M, Cleries R (2004) Primary liver cancer: worldwide incidence and trends. Gastroenterology 127(5 Suppl 1):S5–S16

    PubMed  Article  Google Scholar 

  10. Ma WL, Hsu CL, Wu MH, Wu CT, Wu CC, Lai JJ, Jou YS, Chen CW, Yeh S, Chang C (2008) Androgen receptor is a new potential therapeutic target for the treatment of hepatocellular carcinoma. Gastroenterology 135(3):947–955. doi:10.1053/j.gastro.2008.05.046 955 e941–945

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  11. Ryu WS, Kim JH, Jang YJ, Park SS, Um JW, Park SH, Kim SJ, Mok YJ, Kim CS (2012) Expression of estrogen receptors in gastric cancer and their clinical significance. J Surg Oncol 106(4):456–461. doi:10.1002/jso.23097

    CAS  PubMed  Article  Google Scholar 

  12. Takano N, Iizuka N, Hazama S, Yoshino S, Tangoku A, Oka M (2002) Expression of estrogen receptor-alpha and -beta mRNAs in human gastric cancer. Cancer Lett 176(2):129–135

    CAS  PubMed  Article  Google Scholar 

  13. Wang M, Pan JY, Song GR, Chen HB, An LJ, Qu SX (2007) Altered expression of estrogen receptor alpha and beta in advanced gastric adenocarcinoma: correlation with prothymosin alpha and clinicopathological parameters. Eur J Surg Oncol 33(2):195–201. doi:10.1016/j.ejso.2006.09.009

    CAS  PubMed  Article  Google Scholar 

  14. Xu CY, Guo JL, Jiang ZN, Xie SD, Shen JG, Shen JY, Wang LB (2010) Prognostic role of estrogen receptor alpha and estrogen receptor beta in gastric cancer. Ann Surg Oncol 17(9):2503–2509. doi:10.1245/s10434-010-1031-2

    CAS  PubMed  Article  Google Scholar 

  15. Feng H, Cheng AS, Tsang DP, Li MS, Go MY, Cheung YS, Zhao GJ, Ng SS, Lin MC, Yu J, Lai PB, To KF, Sung JJ (2011) Cell cycle-related kinase is a direct androgen receptor-regulated gene that drives beta-catenin/T cell factor-dependent hepatocarcinogenesis. J Clin Investig 121(8):3159–3175. doi:10.1172/JCI45967

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  16. Okabe H, Satoh S, Kato T, Kitahara O, Yanagawa R, Yamaoka Y, Tsunoda T, Furukawa Y, Nakamura Y (2001) Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. Cancer Res 61(5):2129–2137

    CAS  PubMed  Google Scholar 

  17. Tsou AP, Chuang YC, Su JY, Yang CW, Liao YL, Liu WK, Chiu JH, Chou CK (2003) Overexpression of a novel imprinted gene, PEG10, in human hepatocellular carcinoma and in regenerating mouse livers. J Biomed Sci 10(6 Pt 1):625–635

    CAS  PubMed  Google Scholar 

  18. Okabe H, Satoh S, Furukawa Y, Kato T, Hasegawa S, Nakajima Y, Yamaoka Y, Nakamura Y (2003) Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1. Cancer Res 63(12):3043–3048

    CAS  PubMed  Google Scholar 

  19. Chunsong H, Yuling H, Li W, Jie X, Gang Z, Qiuping Z, Qingping G, Kejian Z, Li Q, Chang AE, Youxin J, Jinquan T (2006) CXC chemokine ligand 13 and CC chemokine ligand 19 cooperatively render resistance to apoptosis in B cell lineage acute and chronic lymphocytic leukemia CD23+ CD5+ B cells. J Immunol 177(10):6713–6722

    PubMed  Article  Google Scholar 

  20. Xiong J, Qin J, Zheng Y, Peng X, Luo Y, Meng X (2012) PEG10 promotes the migration of human Burkitt’s lymphoma cells by up-regulating the expression of matrix metalloproteinase-2 and -9. Clin Invest Med 35(3):E117–E125

    CAS  PubMed  Google Scholar 

  21. O’Neill PA, Davies MP, Shaaban AM, Innes H, Torevell A, Sibson DR, Foster CS (2004) Wild-type oestrogen receptor beta (ERbeta1) mRNA and protein expression in Tamoxifen-treated post-menopausal breast cancers. Br J Cancer 91(9):1694–1702

    PubMed Central  PubMed  Google Scholar 

  22. Morgan M, Kniss D, McDonnell S (1998) Expression of metalloproteinases and their inhibitors in human trophoblast continuous cell lines. Exp Cell Res 242(1):18–26

    CAS  PubMed  Article  Google Scholar 

  23. Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM (2000) Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 18(5):1135–1149

    CAS  PubMed  Google Scholar 

  24. Kalaitzidis D, Gilmore TD (2005) Transcription factor cross-talk: the estrogen receptor and NF-kappaB. Trends Endocrinol Metab 16(2):46–52

    CAS  PubMed  Article  Google Scholar 

  25. Hayden MS, Ghosh S (2004) Signaling to NF-kappaB. Genes Dev 18(18):2195–2224

    CAS  PubMed  Article  Google Scholar 

  26. Dai Y, Chen S, Wang L, Pei XY, Funk VL, Kramer LB, Dent P, Grant S (2011) Disruption of IkappaB kinase (IKK)-mediated RelA serine 536 phosphorylation sensitizes human multiple myeloma cells to histone deacetylase (HDAC) inhibitors. J Biol Chem 286(39):34036–34050

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  27. Brekman A, Singh KE, Polotskaia A, Kundu N, Bargonetti J (2011) A p53-independent role of Mdm2 in estrogen-mediated activation of breast cancer cell proliferation. Breast Cancer Res 13(1):R3

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  28. Chaudhri RA, Olivares-Navarrete R, Cuenca N, Hadadi A, Boyan BD, Schwartz Z (2012) Membrane estrogen signaling enhances tumorigenesis and metastatic potential of breast cancer cells via estrogen receptor-alpha36 (ERalpha36). J Biol Chem 287(10):7169–7181. doi:10.1074/jbc.M111.292946

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  29. Roy R, Moses MA (2012) ADAM12 induces estrogen-independence in breast cancer cells. Breast Cancer Res Treat 131(3):731–741. doi:10.1007/s10549-011-1431-4

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  30. Moore RL, Faller DV (2013) SIRT1 represses estrogen-signaling, ligand-independent ERalpha-mediated transcription, and cell proliferation in estrogen-responsive breast cells. J Endocrinol 216(3):273–285

    CAS  PubMed  Article  Google Scholar 

  31. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35(4):495–516. doi:10.1080/01926230701320337

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  32. Catz SD, Johnson JL (2001) Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene 20(50):7342–7351. doi:10.1038/sj.onc.1204926

    CAS  PubMed  Article  Google Scholar 

  33. Cheng JC, Chou CH, Kuo ML, Hsieh CY (2006) Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene 25(53):7009–7018. doi:10.1038/sj.onc.1209706

    CAS  PubMed  Article  Google Scholar 

  34. Zhou J, Teng R, Xu C, Wang Q, Guo J, Xu C, Li Z, Xie S, Shen J, Wang L (2013) Overexpression of ER alpha inhibits proliferation and invasion of MKN28 gastric cancer cells by suppressing beta-catenin. Oncol Rep 30(4):1622–1630. doi:10.3892/or.2013.2610

    CAS  PubMed  Google Scholar 

  35. Xu H, Wei Y, Zhang Y, Xu Y, Li F, Liu J, Zhang W, Han X, Tan R, Shen P (2012) Oestrogen attenuates tumour progression in hepatocellular carcinoma. J Pathol 228(2):216–229. doi:10.1002/path.4009

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

Q. J. and L. M. contributed equally to this work. The study was supported by the Hubei Province Natural Science Foundation of China (No. 2012FFB04316), the National Natural Science Foundation of China (No. 30801336 and No. 81102863), and The Incubator Project of Renmin Hospital Wuhan University (2013RMFH008). All authors of the manuscript have contributed to this work.

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Correspondence to Jie Xiong.

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Jian Qin and Min Liu have contributed equally to this work.

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Qin, J., Liu, M., Ding, Q. et al. The direct effect of estrogen on cell viability and apoptosis in human gastric cancer cells. Mol Cell Biochem 395, 99–107 (2014). https://doi.org/10.1007/s11010-014-2115-2

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  • DOI: https://doi.org/10.1007/s11010-014-2115-2

Keywords

  • Gender disparity
  • Estrogen
  • Estrogen receptor
  • Apoptosis
  • PEG10