Abstract
Background
Esophageal squamous cell carcinoma (ESCC) is one of the most frequently diagnosed cancers in China, but the etiology and mode of carcinogenesis of this disease remain poorly understood. The phosphatase and tensin homolog deleted from chromosome 10 (PTEN) with putative tumor suppressing is frequently mutated in many cancers.
Aims
The aim of this study was to investigate whether there exists a mutation in the PTEN gene of the ESCC cells, and the effects of the wild type and mutated PTEN genes on the proliferation and apoptosis of the ESCC cells.
Methods
The wild type and mutated PTEN genes were cloned from human placenta and ESCC cells, respectively, and their effects on the proliferation and apoptosis of the ESCC cells were investigated. Also, the relationship between the PTEN gene status and sensitivity of the EC9706 cells to cisplatin was determined in the xenografts of nude mice.
Results
There were mutations in the PTEN gene from ESCC cells. The proliferation of the EC9706 cells was clearly inhibited by the wild type PTEN gene, but not by the mutated PTEN gene in vitro. Furthermore, the wild type PTEN gene inhibited the growth of transplantable tumor, induced cell apoptosis, and improved the sensitivity of the EC9706 cells to cisplatin in vivo.
Conclusion
The findings of the present study demonstrate that there are mutations in the PTEN gene of the ESCC cells and that the wild type PTEN gene has important effects on the ESCC cells in vitro and in vivo.
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References
Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer. 1999;80:827–841.
Montesano R, Hollstein M, Hainaut P. Genetic alterations in esophageal cancer and their relevance to etiology and pathogenesis: a review. Int J Cancer. 1996;69:225–235.
Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, Tavtigian SV. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15:356–362.
Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–1947.
Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998;273:13375–13378.
Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–1657.
Kwon CH, Zhu XY, Zhang JY, Baker SJ. mTor is required for hypertrophy of Pten-deficient neuronal soma in vivo. Proc Natl Acad Sci USA. 2003;100:12923–12928.
Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. J Med Genet. 2004;41:323–326.
Chang D, Wang TY, Li HC, Wei JC, Song JX. Prognostic significance of PTEN expression in esophageal squamous cell carcinoma from Linzhou City, a high incidence area of northern China. Dis Esophagus. 2007;20:491–496.
Ge H, Cao YY, Chen LQ, Wang YM, Chen ZF, Wen DG, Zhang XF, Guo W, Wang N, Li Y, Zhang JH. PTEN polymorphisms and the risk of esophageal carcinoma and gastric cardiac carcinoma in a high incidence region of China. Dis Esophagus. 2008;21:409–415.
Tian F, Zang WD, Hou WH, Liu HT, Xue LX. Nuclear factor-kB signaling pathway constitutively activated in esophageal squamous cell carcinoma cell lines and inhibition of growth of cells by small interfering RNA. Acta Biochim Biophys Sin. 2006;38:318–326.
Hou G, Xue L, Lu Z, Fan T, Tian F, Xue Y. An activated mTOR/p70S6K signaling pathway in esophageal squamous cell carcinoma cell lines and inhibition of the pathway by rapamycin and siRNA against mTOR. Cancer Lett. 2007;253:236–248.
Zor T, Selinger Z. Linearization of the Bradford protein assay increases its sensitivity: theoretical and experimental studies. Anal Biochem. 1996;236:302–308.
Smolewski P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway. Anticancer Drugs. 2006;17:487–494.
Fiebig HH, Berger DP, Winterhalter BR, Plowman J. In vitro and in vivo evaluation of US-NCI compounds in human tumor xenografts. Cancer Treat Rev. 1990;17:109–117.
Amornphimoltham P, Patel V, Sodhi A, Nikitakis NG, Sauk JJ, Sausville EA, Molinolo AA, Gutkind JS. Mammalian target of rapamycin, a molecular target in squamous cell carcinomas of the head and neck. Cancer Res. 2005;65:9953–9961.
Hou G, Zhang Q, Wang L, Liu M, Wang J, Xue L. mTOR inhibitor rapamycin alone or combined with cisplatin inhibits growth of esophageal squamous cell carcinoma in nude mice. Cancer Lett. 2010;290:248–254.
Ittmann MM. Chromosome 10 alterations in prostate adenocarcinoma (review). Oncol Rep. 1998;5:1329–1335.
Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen KL, Vinson VL, Gumpper KL, Ellis L, El-Naggar A, Frazier M, Jasser S, Langford LA, Lee J, Mills GB, Pershouse MA, Pollack RE, Tornos C, Troncoso P, Yung WK, Fujii G, Berson A, Steck PA. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res. 1997;57:5221–5225.
McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR. Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res. 1999;59:4291–4296.
Lee JO, Yang H, Georgescu MM, Di Cristofano A, Maehama T, Shi Y, Dixon JE, Pandolfi P, Pavletich NP. Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association. Cell. 1999;99:323–334.
Yamada KM, Araki M. Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J Cell Sci. 2001;114:2375–2382.
Chu EC, Tarnawski AS. PTEN regulatory functions in tumor suppression and cell biology. Med Sci Monit. 2004;10:RA235–RA241.
Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci USA. 1998;95:15587–15591.
Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.
Weng LP, Brown JL, Eng C. PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. Hum Mol Genet. 2001;10:599–604.
Navé BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J. 1999;344:427–431.
Brunn GJ, Hudson CC, Sekulić A, Williams JM, Hosoi H, Houghton PJ, Lawrence JC Jr, Abraham RT. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science. 1997;277:99–101.
Cao C, Subhawong T, Albert JM, Kim KW, Geng L, Sekhar KR, Gi YJ, Lu B. Inhibition of mammalian target of rapamycin or apoptotic pathway induces autophagy and radiosensitizes PTEN null prostate cancer cells. Cancer Res. 2006;66:10040–10047.
Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA. 2001;98:10314–10319.
Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J, Neshat M, Wang H, Yang L, Gibbons J, Frost P, Dreisbach V, Blenis J, Gaciong Z, Fisher P, Sawyers C, Hedrick-Ellenson L, Parsons R. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/−mice. Proc Natl Acad Sci USA. 2001;98:10320–10325.
Hu YC, Lam KY, Tang JC, Srivastava G. Mutational analysis of the PTEN/MMAC1 gene in primary oesophageal squamous cell carcinomas. Mol Pathol. 1999;52:353–356.
Ding Y, Shimada Y, Kano M, Itami A, Kawabe A, Maeda M, Li Z, Hong T, Sato F, Kaganoi J, Imamura M. PTEN/MMAC1 expression in esophageal squamous cell carcinomas. Int J Oncol. 2000;17:695–699.
Acknowledgments
This study was supported by grants from the National Natural Science Foundation of China (no. 30901778), Fund for Introduced Talented Persons of Zhengzhou University, and the “211 Project” of the 10th Five-Year Plan (Education Ministry of China, 2002-2).
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There are no conflicts of interest regarding this paper.
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Hou, G., Lu, Z., Liu, M. et al. Mutational Analysis of the PTEN Gene and Its Effects in Esophageal Squamous Cell Carcinoma. Dig Dis Sci 56, 1315–1322 (2011). https://doi.org/10.1007/s10620-010-1474-0
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DOI: https://doi.org/10.1007/s10620-010-1474-0