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Article

Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma

  • Authors:
    • Hai Yan Yang
    • Li Ying Xue
    • Ling Xiao Xing
    • Juan Wang
    • Jun Ling Wang
    • Xia Yan
    • Xiang Hong Zhang
  • View Affiliations / Copyright

    Affiliations: Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang 050000, P.R. China, Department of Pathology, Hebei Medical University, Shijiazhuang 050017, P.R. China
  • Pages: 537-542
    |
    Published online on: November 28, 2012
       https://doi.org/10.3892/mmr.2012.1208
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Abstract

The mammalian target of rapamycin/eukaryotic translation inititiation factor 4E binding protein 1 (mTOR/4E-BP1) transduction pathway is activated in a range of malignant cancers, but its role in human gastric cardiac adenocarcinoma (GCA) has not been well defined. The present study used western blotting and reverse transcription polymerase chain reaction (RT-PCR) to assess the expression of mTOR, 4E-BP1 and eukaryotic translation initiation factor 4E (eIF4E) at the protein and mRNA levels in 33 cases of GCA and paired adjacent normal gastric mucosal tissues. The expression of mTOR at the protein level in GCA was significantly lower than that in the corresponding normal gastric mucosa (0.296±0.27 vs. 1.348±0.80, P<0.05), but the ratio of p-mTOR to mTOR was significantly increased in tumor tissues (1.425±1.07 vs. 0.450±0.24, P<0.05). The expression of 4E-BP1 was significantly decreased in GCA compared with normal tissues (p<0.05), while the levels of phosphorylated 4E-BP1 (p-4E-BP1) were markedly increased in tumor tissues (p<0.05). The levels of phosphorylated eIF4E (p‑eIF4E) were significantly higher in the tumors in comparison to the corresponding normal tissues (1.822±0.63 vs. 0.997±0.38, P<0.05), and the levels of p-eIF4E were closely correlated with lymph node metastasis (p<0.05). The mTOR/4E-BP1 signaling pathway is activated in GCA, with mTOR activated mainly through increased mTOR phosphorylation rather than protein overexpression.
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1 

Shah MA and Schwartz GK: Treatment of metastatic esophagus and gastric cancer. Semin Oncol. 31:574–587. 2004. View Article : Google Scholar : PubMed/NCBI

2 

Crane SJ, Richard Locke G III, Harmsen WS, Diehl NN, Zinsmeister AR, Joseph Melton L III, et al: The changing incidence of oesophageal and gastric adenocarcinoma by anatomic sub-site. Aliment Pharmacol Ther. 25:447–453. 2007. View Article : Google Scholar : PubMed/NCBI

3 

Zhao CY, Zhang XH, Xue LY, Xing LX, Wang JL, Li XM, et al: Analysis of the changing trends of frequency and localization of gastric cancers arising from different sites of the stomach in population of the high incidence area of esophageal and gastric cancers in Hebei province. Zhonghua Zhong Liu Za Zhi. 30:817–820. 2008.(In Chinese).

4 

Tajima Y, Yamazaki K, Makino R, Nishino N, Masuda Y, Aoki S, et al: Differences in the histological findings, phenotypic marker expressions and genetic alterations between adenocarcinoma of the gastric cardia and distal stomach. Br J Cancer. 96:631–638. 2007. View Article : Google Scholar

5 

Faried LS, Faried A, Kanuma T, Aoki H, Sano T, Nakazato T, et al: Expression of an activated mammalian target of rapamycin in adenocarcinoma of the cervix: A potential biomarker and molecular target therapy. Mol Carcinog. 47:446–457. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Albert JM, Kim KW, Cao C and Lu B: Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer. Mol Cancer Ther. 5:1183–1189. 2006.

7 

Mori H, Inoki K, Masutani K, Wakabayashi Y, Komai K, Nakagawa R, et al: The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem Biophys Res Commun. 384:471–475. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Fingar DC and Blenis J: Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene. 23:3151–3171. 2004. View Article : Google Scholar : PubMed/NCBI

9 

Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C and Blenis J: mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 24:200–216. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Azar R, Alard A, Susini C, Bousquet C and Pyronnet S: 4E-BP1 is a target of Smad4 essential for TGFbeta-mediated inhibition of cell proliferation. EMBO J. 28:3514–3522. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Oulhen N, Mulner-Lorillon O and Cormier P: eIF4E-binding proteins are differentially modified after ammonia versus intracellular calcium activation of sea urchin unfertilized eggs. Mol Reprod Dev. 77:83–91. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Lang SA, Gaumann A, Koehl GE, Seidel U, Bataille F, Klein D, et al: Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model. Int J Cancer. 120:1803–1810. 2007. View Article : Google Scholar : PubMed/NCBI

13 

Yoon DH, Ryu MH, Park YS, Lee HJ, Lee C, Ryoo BY, et al: Phase II study of everolimus with biomarker exploration in patients with advanced gastric cancer refractory to chemotherapy including fluoropyrimidine and platinum. Br J Cancer. 106:1039–1044. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Siewert JR and Stein HJ: Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg. 85:1457–1459. 1998. View Article : Google Scholar : PubMed/NCBI

15 

Johnson SM, Gulhati P, Rampy BA, Han Y, Rychahou PG, Doan HQ, et al: Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J Am Coll Surg. 210:767–776. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Kruck S, Bedke J, Hennenlotter J, Ohneseit PA, Kuehs U, Senger E, et al: Activation of mTOR in renal cell carcinoma is due to increased phosphorylation rather than protein overexpression. Oncol Rep. 23:159–163. 2010.PubMed/NCBI

17 

Zhou X, Tan M, Stone Hawthorne V, Klos KS, Lan KH, Yang Y, et al: Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res. 10:6779–6788. 2004. View Article : Google Scholar : PubMed/NCBI

18 

Ji J and Zheng PS: Activation of mTOR signaling pathway contributes to survival of cervical cancer cells. Gynecol Oncol. 117:103–108. 2010. View Article : Google Scholar : PubMed/NCBI

19 

Faivre S, Kroemer G and Raymond E: Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 5:671–688. 2006. View Article : Google Scholar : PubMed/NCBI

20 

Osaki M, Kase S, Adachi K, Takeda A, Hashimoto K and Ito H: Inhibition of the PI3K-Akt signaling pathway enhances the sensitivity of Fas-mediated apoptosis in human gastric carcinoma cell line, MKN-45. J Cancer Res Clin Oncol. 130:8–14. 2004. View Article : Google Scholar : PubMed/NCBI

21 

Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein-Szanto AJ, Godwin AK and Testa JR: AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene. 23:5853–5857. 2004. View Article : Google Scholar : PubMed/NCBI

22 

Yu G, Wang J, Chen Y, Wang X, Pan J, Li G, et al: Overexpression of phosphorylated mammalian target of rapamycin predicts lymph node metastasis and prognosis of chinese patients with gastric cancer. Clin Cancer Res. 15:1821–1829. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Murayama T, Inokuchi M, Takagi Y, Yamada H, Kojima K, Kumagai J, et al: Relation between outcomes and localisation of p-mTOR expression in gastric cancer. Br J Cancer. 100:782–788. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Fingar DC, Salama S, Tsou C, Harlow E and Blenis J: Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes Dev. 16:1472–1487. 2002. View Article : Google Scholar : PubMed/NCBI

25 

Sabatini DM: mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. 6:729–734. 2006. View Article : Google Scholar : PubMed/NCBI

26 

Kremer CL, Klein RR, Mendelson J, Browne W, Samadzedeh LK, Vanpatten K, et al: Expression of mTOR signaling pathway markers in prostate cancer progression. Prostate. 66:1203–1212. 2006. View Article : Google Scholar : PubMed/NCBI

27 

Armengol G, Rojo F, Castellvi J, Iglesias C, Cuatrecasas M, Pons B, et al: 4E-binding protein 1: a key molecular ‘funnel factor’ in human cancer with clinical implications. Cancer Res. 67:7551–7555. 2007.

28 

Darb-Esfahani S, Faggad A, Noske A, Weichert W, Buckendahl AC, Müller B, et al: Phospho-mTOR and phospho-4EBP1 in endometrial adenocarcinoma: association with stage and grade in vivo and link with response to rapamycin treatment in vitro. J Cancer Res Clin Oncol. 135:933–941. 2009. View Article : Google Scholar : PubMed/NCBI

29 

O’Reilly KE, Warycha M, Davies MA, Rodrik V, Zhou XK, Yee H, et al: Phosphorylated 4E-BP1 is associated with poor survival in melanoma. Clin Cancer Res. 15:2872–2878. 2009.PubMed/NCBI

30 

Benavente S, Vergés R, Hermosilla E, Fumanal V, Casanova N, García A, et al: Overexpression of phosphorylated 4E-BP1 predicts for tumor recurrence and reduced survival in cervical carcinoma treated with postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 75:1316–1322. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Mamane Y, Petroulakis E, Rong L, Yoshida K, Ler LW and Sonenberg N: eIF4E - from translation to transformation. Oncogene. 23:3172–3179. 2004. View Article : Google Scholar : PubMed/NCBI

32 

Sonenberg N: Cap-binding proteins of eukaryotic messenger RNA: functions in initiation and control of translation. Prog Nucleic Acid Res Mol Biol. 35:173–207. 1988. View Article : Google Scholar : PubMed/NCBI

33 

De Benedetti A and Harris AL: eIF4E expression in tumors: its possible role in progression of malignancies. Int J Biochem Cell Biol. 31:59–72. 1999.PubMed/NCBI

34 

Culjkovic B, Topisirovic I and Borden KL: Controlling gene expression through RNA regulons: the role of the eukaryotic translation initiation factor eIF4E. Cell Cycle. 6:65–69. 2007. View Article : Google Scholar : PubMed/NCBI

35 

De Benedetti A and Graff JR: eIF4E expression and its role in malignancies and metastases. Oncogene. 23:3189–3199. 2004.PubMed/NCBI

36 

Wang R, Geng J, Wang JH, Chu XY, Geng HC and Chen LB: Overexpression of eukaryotic initiation factor 4E (eIF4E) and its clinical significance in lung adenocarcinoma. Lung Cancer. 66:237–244. 2009. View Article : Google Scholar : PubMed/NCBI

37 

Topisirovic I, Ruiz-Gutierrez M and Borden KL: Phosphorylation of the eukaryotic translation initiation factor eIF4E contributes to its transformation and mRNA transport activities. Cancer Res. 64:8639–8642. 2004. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Yang HY, Xue LY, Xing LX, Wang J, Wang JL, Yan X and Zhang XH: Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma. Mol Med Rep 7: 537-542, 2013.
APA
Yang, H.Y., Xue, L.Y., Xing, L.X., Wang, J., Wang, J.L., Yan, X., & Zhang, X.H. (2013). Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma. Molecular Medicine Reports, 7, 537-542. https://doi.org/10.3892/mmr.2012.1208
MLA
Yang, H. Y., Xue, L. Y., Xing, L. X., Wang, J., Wang, J. L., Yan, X., Zhang, X. H."Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma". Molecular Medicine Reports 7.2 (2013): 537-542.
Chicago
Yang, H. Y., Xue, L. Y., Xing, L. X., Wang, J., Wang, J. L., Yan, X., Zhang, X. H."Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma". Molecular Medicine Reports 7, no. 2 (2013): 537-542. https://doi.org/10.3892/mmr.2012.1208
Copy and paste a formatted citation
x
Spandidos Publications style
Yang HY, Xue LY, Xing LX, Wang J, Wang JL, Yan X and Zhang XH: Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma. Mol Med Rep 7: 537-542, 2013.
APA
Yang, H.Y., Xue, L.Y., Xing, L.X., Wang, J., Wang, J.L., Yan, X., & Zhang, X.H. (2013). Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma. Molecular Medicine Reports, 7, 537-542. https://doi.org/10.3892/mmr.2012.1208
MLA
Yang, H. Y., Xue, L. Y., Xing, L. X., Wang, J., Wang, J. L., Yan, X., Zhang, X. H."Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma". Molecular Medicine Reports 7.2 (2013): 537-542.
Chicago
Yang, H. Y., Xue, L. Y., Xing, L. X., Wang, J., Wang, J. L., Yan, X., Zhang, X. H."Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma". Molecular Medicine Reports 7, no. 2 (2013): 537-542. https://doi.org/10.3892/mmr.2012.1208
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