Insulin-like growth factor-I induces epithelial to mesenchymal transition via GSK-3β and ZEB2 in the BGC-823 gastric cancer cell line

Li,Heming; Xu,Ling; Zhao,Lei; Ma,Yanju; Zhu,Zhitu; Liu,Yunpeng; Qu,Xiujuan

doi:10.3892/ol.2014.2687

Insulin-like growth factor-I induces epithelial to mesenchymal transition via GSK-3β and ZEB2 in the BGC-823 gastric cancer cell line

Authors:
- Heming Li
- Ling Xu
- Lei Zhao
- Yanju Ma
- Zhitu Zhu
- Yunpeng Liu
- Xiujuan Qu
View Affiliations

Affiliations: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China, Department of Oncology, The First Affiliated Hospital of Liaoning Medical University, Jinzhou, Liaoning 121001, P.R. China
Published online on: November 7, 2014 https://doi.org/10.3892/ol.2014.2687
Pages: 143-148

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

Metastasis is the most common cause of mortality in patients with gastric cancer. Epithelial-to-mesenchymal transition (EMT), which may be stimulated by insulin-like growth factor-I (IGF-I) is involved in the metastasis of numerous tumors; however, the molecular mechanism by which IGF‑I may induce tumor cell EMT remains to be elucidated in gastric cancer. The present study aimed to investigate the induction of EMT in BGC‑823 gastric cancer cells. It was identified that IGF‑I induced EMT by upregulating the levels of ZEB2 transcription factor, and this was dependent on the phosphoinositide 3‑kinase (PI3K)/Akt signaling pathway in these cells. In addition, glycogen synthase kinase 3β (GSK‑3β), an intracellular downstream effector of PI3K/Akt, sustained the epithelial phenotype by repressing ZEB2 expression and the subsequent inhibition of EMT induced by IGF‑I, suggesting the involvement of a potential PI3K/Akt‑GSK‑3β‑ZEB2 signaling pathway in IGF‑I‑induced EMT in gastric cancer BGC‑823 cells. Overall, the results of the present study suggest that IGF‑I induced EMT by the activation of a PI3K/Akt‑GSK‑3β‑ZEB2 signaling pathway in gastric cancer BGC‑823 cells. Therefore, this study may provide more useful information regarding the mechanism of gastric cancer metastasis.

View Figures

View References

1	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar : PubMed/NCBI
2	Crew KD and Neugut AI: Epidemiology of gastric cancer. World J Gastroenterol. 12:354–362. 2006.PubMed/NCBI
3	Chen W, Zheng R, Zhang S, Zhao P, Li G, Wu L and He J: The incidences and mortalities of major cancers in China, 2009. Chin J Cancer. 32:106–112. 2013. View Article : Google Scholar : PubMed/NCBI
4	Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A and Fleig WE: Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol. 24:2903–2909. 2006. View Article : Google Scholar : PubMed/NCBI
5	Thompson EW, Newgreen DF and Tarin D: Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res. 65:5991–5995. 2005. View Article : Google Scholar : PubMed/NCBI
6	Wang Y, Wen M, Kwon Y, et al: CUL4A induces epithelial-mesenchymal transition and promotes cancer metastasis by regulating ZEB1 expression. Cancer Res. 74:520–531. 2014. View Article : Google Scholar
7	Lee JM, Dedhar S, Kalluri R and Thompson EW: The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 172:973–981. 2006. View Article : Google Scholar : PubMed/NCBI
8	Graham TR, Zhau HE, Odero-Marah VA, et al: Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 68:2479–2488. 2008. View Article : Google Scholar : PubMed/NCBI
9	Walsh LA and Damjanovski S: IGF-1 increases invasive potential of MCF 7 breast cancer cells and induces activation of latent TGF-β1 resulting in epithelial to mesenchymal transition. Cell Commun Signal. 9:102011. View Article : Google Scholar
10	Lorenzatti G, Huang W, Pal A, Cabanillas AM and Kleer CG: CCN6 (WISP3) decreases ZEB1-mediated EMT and invasion by attenuation of IGF-1 receptor signaling in breast cancer. J Cell Sci. 124:1752–1758. 2011. View Article : Google Scholar : PubMed/NCBI
11	Adachi Y, Li R, Yamamoto H, et al: Insulin-like growth factor-I receptor blockade reduces the invasiveness of gastrointestinal cancers via blocking production of matrilysin. Carcinogenesis. 30:1305–1313. 2009. View Article : Google Scholar : PubMed/NCBI
12	Ge J, Chen Z, Wu S, et al: Expression levels of insulin-like growth factor-1 and multidrug resistance-associated protein-1 indicate poor prognosis in patients with gastric cancer. Digestion. 80:148–158. 2009. View Article : Google Scholar : PubMed/NCBI
13	Franciosi CM, Piacentini MG, Conti M, et al: IGF-1 and IGF-1BP3 in gastric adenocarcinoma. Preliminary study. Hepatogastroenterology. 50:297–300. 2003.PubMed/NCBI
14	Robertson JF, Ferrero JM, Bourgeois H, et al: Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet Oncol. 14:228–235. 2013. View Article : Google Scholar : PubMed/NCBI
15	Trajkovic-Arsic M, Kalideris E and Siveke JT: The role of insulin and IGF system in pancreatic cancer. J Mol Endocrinol. 50:R67–R74. 2013. View Article : Google Scholar : PubMed/NCBI
16	Kim HJ, Litzenburger BC, Cui X, et al: Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and snail. Mol Cell Biol. 27:3165–3175. 2007. View Article : Google Scholar : PubMed/NCBI
17	Sivakumar R, Koga H, Selvendiran K, Maeyama M, Ueno T and Sata M: Autocrine loop for IGF-I receptor signaling in SLUG-mediated epithelial-mesenchymal transition. Int J Oncol. 34:329–338. 2009.PubMed/NCBI
18	Irie HY, Pearline RV, Grueneberg D, et al: Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol. 171:1023–1034. 2005. View Article : Google Scholar : PubMed/NCBI
19	Papkoff J and Aikawa M: WNT-1 and HGF regulate GSK3 beta activity and beta-catenin signaling in mammary epithelial cells. Biochem Biophys Res Commun. 247:851–858. 1998. View Article : Google Scholar : PubMed/NCBI
20	Sineva GS and Pospelov VA: Inhibition of GSK3beta enhances both adhesive and signalling activities of beta-catenin in mouse embryonic stem cells. Biol Cell. 102:549–560. 2010. View Article : Google Scholar : PubMed/NCBI
21	Ho MY, Tang SJ, Chuang MJ, Cha TL, Li JY, Sun GH and Sun KH: TNF-α induces epithelial-mesenchymal transition of renal cell carcinoma cells via a GSK3β-dependent mechanism. Mol Cancer Res. 10:1109–1119. 2012. View Article : Google Scholar : PubMed/NCBI
22	Zheng H, Li W and Wang Y: Glycogen synthase kinase-3 beta regulates Snail and β-catenin expression during Fas-induced epithelial-mesenchymal transition in gastrointestinal cancer. Eur J Cancer. 49:2734–2746. 2013. View Article : Google Scholar : PubMed/NCBI
23	Lowry OH, Rosebrough NJ, Farr AL and Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem. 193:265–275. 1951.PubMed/NCBI
24	Miyoshi A, Kitajima Y, Sumi K, Sato K, Hagiwara A, Koga Y and Miyazaki K: Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells. Br J Cancer. 90:1265–1273. 2004. View Article : Google Scholar : PubMed/NCBI
25	Remacle JE, Kraft H, Lerchner W, et al: New mode of DNA binding of multi-zinc finger transcription factors: deltaEF1 family members bind with two hands to two target sites. EMBO J. 18:5073–5084. 1999. View Article : Google Scholar : PubMed/NCBI
26	Elloul S, Elstrand MB, Nesland JM, et al: Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer. 103:1631–1643. 2005. View Article : Google Scholar : PubMed/NCBI
27	Mikaelian I, Malek M, Gadet R, et al: Genetic and pharmacologic inhibition of mTORC1 promotes EMT by a TGF-β-independent mechanism. Cancer Res. 73:6621–6631. 2013. View Article : Google Scholar : PubMed/NCBI
28	Gregory PA, Bracken CP, Smith E, et al: An autocrine TGF- beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol Biol Cell. 22:1686–1698. 2011. View Article : Google Scholar : PubMed/NCBI