EGCG inhibits recepteur d'origine nantais expression by suppressing Egr-1 in gastric cancer cells

Park,Jung  Sun; Khoi,Pham  Ngoc; Joo,Young  Eun; Lee,Young  Han; Lang,Sven  A.; Stoeltzing,Oliver; Jung,Young  Do

doi:10.3892/ijo.2013.1775

EGCG inhibits recepteur d'origine nantais expression by suppressing Egr-1 in gastric cancer cells

Authors:
- Jung Sun Park
- Pham Ngoc Khoi
- Young Eun Joo
- Young Han Lee
- Sven A. Lang
- Oliver Stoeltzing
- Young Do Jung
View Affiliations

Affiliations: Research Institute of Medical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea, Department of Biomedical Science and Technology, SMART Institute of Advanced Biomedical Science, RCTC, Konkuk University, Seoul, Republic of Korea, Department of Surgery, University Medical Center Regensburg, Regensburg, Germany, Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Published online on: January 16, 2013 https://doi.org/10.3892/ijo.2013.1775
Pages: 1120-1126

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

Abnormal accumulation and activation of the recepteur d'origine nantais (RON) has been implicated in epithelial tumor carcinogenesis. In the present study, we examined the effect of epigallocatechin-3-gallate (EGCG), the major green tea catechin, on the induction of RON and tumor growth in human gastric cancer. EGCG inhibited phorbol 12‑myristate 13‑acetate (PMA)‑induced RON expression and reduced RON transcriptional activity. However, (-)‑epigallocatechin (EGC), (-)‑epicatechin gallate (ECG) and (-)‑epicatechin (EC) did not affect RON expression. Experiments with deleted and site‑directed mutagenesis of the RON promoter indicated that Egr-1 binding sites in the RON promoter may be the EGCG‑response element acting as a cis‑element in gastric cancer cells. EGCG also inhibited PMA-induced Egr-1 expression and DNA binding in a dose-dependent manner. Furthermore, gastric cancer cells pretreated with PMA showed markedly enhanced invasiveness, which was partially abrogated by EGCG and siRNA‑targeted RON and Egr-1. EGCG significantly reduced tumor growth in an in vivo tumor model, whereas RON expression was downregulated. These results suggest that EGCG may exert at least part of its anticancer effect by controlling RON expression through suppression of Egr-1 activation.

View Figures

View References

1	Sasazuki S, Tamakoshi A, Matsuo K, Ito H, Wakai K, Nagata C, Mizoue T, Tanaka K, Tsuji I, Inoue M and Tsugane S; Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan: Green tea consumption and gastric cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Jpn J Clin Oncol. 42:335–346. 2012. View Article : Google Scholar : PubMed/NCBI
2	Yuan JM, Sun C and Butler LM: Tea and cancer prevention: epidemiological studies. Pharmacol Res. 64:123–135. 2011. View Article : Google Scholar : PubMed/NCBI
3	Stoner GD and Mukhtar H: Polyphenols as cancer chemopreventive agents. J Cell Biochem (Suppl). 22:169–180. 1995. View Article : Google Scholar : PubMed/NCBI
4	Yoo HG, Shin BA, Park JC, Kim HS, Kim WJ, Chay KO, Ahn BW, Park RK, Ellis LM and Jung YD: Induction of apoptosis by the green tea flavonol (-)-epigallocatechin-3-gallate in human endothelial ECV 304 cells. Anticancer Res. 22:3373–3378. 2002.PubMed/NCBI
5	Jung YD, Kim MS, Shin BA, Chay KO, Ahn BW, Liu W, Bucana CD, Gallick GE and Ellis LM: EGCG, a major component of green tea, inhibits tumour growth by inhibiting VEGF induction in human colon carcinoma cells. Br J Cancer. 84:844–850. 2001. View Article : Google Scholar : PubMed/NCBI
6	Nagini S: Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol. 4:156–169. 2012. View Article : Google Scholar : PubMed/NCBI
7	Park JS, Park JH, Khoi PN, Joo YE and Jung YD: MSP-induced RON activation upregulates uPAR expression and cell invasiveness via MAPK, AP-1 and NF-κB signals in gastric cancer cells. Carcinogenesis. 32:175–181. 2011.PubMed/NCBI
8	Feres KJ, Ischenko I and Hayman MJ: The RON receptor tyrosine kinase promotes MSP-independent cell spreading and survival in breast epithelial cells. Oncogene. 28:279–288. 2009. View Article : Google Scholar : PubMed/NCBI
9	Wang MH, Ronsin C, Gesnel MC, Coupey L, Skeel A, Leonard EJ and Breathnach R: Identification of the ron gene product as the receptor for the human macrophage stimulating protein. Science. 266:117–119. 1994. View Article : Google Scholar : PubMed/NCBI
10	Chen YQ, Zhou YQ, Angeloni D, Kurtz AL, Qiang XZ and Wang MH: Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines. Exp Cell Res. 261:229–238. 2000. View Article : Google Scholar : PubMed/NCBI
11	Wang J, Rajput A, Kan JL, Rose R, Liu XQ, Kuropatwinski K, Hauser J, Beko A, Dominquez I, Sharratt EA, Brattain L, Levea C, Sun FL, Keane DM, Gibson NW and Brattain MG: Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma. J Biol Chem. 284:10912–10922. 2009. View Article : Google Scholar : PubMed/NCBI
12	Leonis MA, Thobe MN and Waltz SE: Ron-receptor tyrosine kinase in tumorigenesis and metastasis. Future Oncol. 3:441–448. 2007. View Article : Google Scholar : PubMed/NCBI
13	Thangasamy A, Rogge J and Ammanamanchi S: Recepteur d’origine nantais tyrosine kinase is a direct target of hypoxiainducible factor-1alpha-mediated invasion of breast carcinoma cells. J Biol Chem. 284:14001–14010. 2009.
14	Lee KE, Park JS, Khoi PN, Joo YE, Lee YH and Jung YD: Upregulation of recepteur d’origine nantais tyrosine kinase and cell invasiveness via early growth response-1 in gastric cancer cells. J Cell Biochem. 113:1217–1223. 2012.
15	Thangasamy A, Rogge J and Ammanamanchi S: Regulation of RON tyrosine kinase-mediated invasion of breast cancer cells. J Biol Chem. 283:5335–5343. 2008. View Article : Google Scholar : PubMed/NCBI
16	Zhou D, Pan G, Zheng C, Zheng J, Yian L and Teng X: Expression of the RON receptor tyrosine kinase and its association with gastric carcinoma versus normal gastric tissues. BMC Cancer. 8:3532008. View Article : Google Scholar : PubMed/NCBI
17	Kono S, Ikeda M, Tokudome S and Kuratsune M: A case-control study of gastric cancer and diet in northern Kyushu, Japan. Jpn J Cancer Res. 79:1067–1074. 1988. View Article : Google Scholar : PubMed/NCBI
18	Rogers AE, Hafer LJ, Iskander YS and Yang S: Black tea and mammary gland carcinogenesis by 7,12-dimethylbenz(a)anthracene in rats fed control or high fat diets. Carcinogenesis. 19:1269–1273. 1998. View Article : Google Scholar : PubMed/NCBI
19	Fujiki H, Suganuma M, Okabe S, Sueoka E, Suga K, Imai K, Nakachi K and Kimura S: Mechanistic findings of green tea as cancer preventive for humans. Proc Soc Exp Biol Med. 220:225–228. 1999. View Article : Google Scholar : PubMed/NCBI
20	Liang YC, Lin-shiau SY, Chen CF and Lin JK: Suppression of extracellular signals and cell proliferation through EGF receptor binding by (-)-epigallocatechin gallate in human A431 epdeidermoid carcinoma cells. J Cell Biochem. 67:55–65. 1997. View Article : Google Scholar
21	Kitano K, Nam KY, Kimura S, Fujiki H and Imanishi Y: Sealing effects of (-)-epigallocatechin gallate on protein kinase C and protein phosphatase 2A. Biophys Chem. 65:157–164. 1997. View Article : Google Scholar : PubMed/NCBI
22	Fu Y and Chen A: The phyto-chemical (-)-epigallocatechin gallate suppresses gene expression of epidermal growth factor receptor in rat hepatic stellate cells in vitro by reducing the activity of Egr-1. Biochem Pharmacol. 72:227–238. 2006. View Article : Google Scholar
23	Moon Y, Lee M and Yang H: Involvement of early growth response gene 1 in the modulation of microsomal prostaglandin E synthase 1 by epigallocatechin gallate in A549 human pulmonary epithelial cells. Biochem Pharmacol. 73:125–135. 2007. View Article : Google Scholar : PubMed/NCBI
24	Thiel G and Cibelli G: Regulation of life and death by the zinc finger transcription factor Egr-1. J Cell Physiol. 193:287–292. 2002. View Article : Google Scholar : PubMed/NCBI
25	Shin SY, Kim JH, Baker A, Lim Y and Lee YH: Transcription factor Egr-1 is essential for maximal matrix metalloproteinase-9 transcription by tumor necrosis factor alpha. Mol Cancer Res. 8:507–519. 2010. View Article : Google Scholar : PubMed/NCBI
26	Keates S, Keates AC, Nath S, Peek RM Jr and Kelly CP: Trans-activation of the epidermal growth factor receptor by cag+ Helicobacter pylori induces upregulation of the early growth response gene Egr-1 in gastric epithelial cells. Gut. 54:1363–1369. 2005.PubMed/NCBI
27	Ma J, Ren Z, Ma Y, Xu L, Zhao Y, Zheng C, Fang Y, Xue T, Sun B and Xiao W: Targeted knockdown of EGR-1 inhibits IL-8 production and IL-8-mediated invasion of prostate cancer cells through suppressing EGR-1/NF-kappaB synergy. J Biol Chem. 284:34600–34606. 2009. View Article : Google Scholar : PubMed/NCBI
28	Kaufmann K and Thiel G: Epidermal growth factor and platelet-derived growth factor induce expression of Egr-1, a zinc finger transcription factor, in human malignant glioma cells. J Neurol Sci. 189:83–91. 2001. View Article : Google Scholar
29	Cohen DM, Gullans SR and Chin WW: Urea inducibility of egr-1 in murine inner medullary collecting duct cells is mediated by the serum response element and adjacent Ets motifs. J Biol Chem. 271:12903–12908. 1996. View Article : Google Scholar : PubMed/NCBI
30	Katiyar SK, Afaq F, Azizuddin K and Mukhtar H: Inhibition of UVB-induced oxidative stress-mediated phosphorylation of mitogen-activated protein kinase signaling pathways in cultured human epidermal keratinocytes by green tea polyphenol (-)-epigallocatechin-3-gallate. Toxicol Appl Pharmacol. 176:110–117. 2001. View Article : Google Scholar
31	Khan HY, Zubair H, Ullah MF, Ahmad A and Hadi SM: Oral administration of copper to rats leads to increased lymphocyte cellular DNA degradation by dietary polyphenols: implications for a cancer preventive mechanism. Biometals. 24:1169–1178. 2011. View Article : Google Scholar
32	Lin JK: Cancer chemoprevention by tea polyphenols through modulating signal transduction pathways. Arch Pharm Res. 25:561–571. 2002. View Article : Google Scholar : PubMed/NCBI
33	O’Toole JM, Rabenau KE, Burns K, Lu D, Mangalampalli V, Balderes P, Covino N, Bassi R, Prewett M, Gottfredsen KJ, Thobe MN, Cheng Y, Li Y, Hicklin DJ, Zhu Z, Waltz SE, Hayman MJ, Ludwig DL and Pereira DS: Therapeutic implications of a human neutralizing antibody to the macrophage-stimulating protein receptor tyrosine kinase (RON), a c-MET family member. Cancer Res. 66:9162–9170. 2006.
34	Logan-Collins J, Thomas RM, Yu P, Jaquish D, Mose E, French R, Stuart W, McClaine R, Aronow B, Hoffman RM, Waltz SE and Lowy AM: Silencing of RON receptor signaling promotes apoptosis and gemcitabine sensitivity in pancreatic cancers. Cancer Res. 70:1130–1140. 2010. View Article : Google Scholar : PubMed/NCBI