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Erschienen in: Pathology & Oncology Research 4/2016

07.05.2016 | Original Article

The Gene Expression Status of the PI3K/AKT/mTOR Pathway in Gastric Cancer Tissues and Cell Lines

verfasst von: Ismael Riquelme, Oscar Tapia, Jaime A. Espinoza, Pamela Leal, Kurt Buchegger, Alejandra Sandoval, Carolina Bizama, Juan Carlos Araya, Richard M. Peek, Juan Carlos Roa

Erschienen in: Pathology & Oncology Research | Ausgabe 4/2016

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Abstract

The PI3K/AKT/mTOR pathway plays a crucial role in the regulation of multiple cellular functions including cell growth, proliferation, metabolism and angiogenesis. Emerging evidence has shown that deregulation of this pathway has a role promoting gastric cancer (GC). The aim was to assess the expression of genes involved in this pathway by qPCR in 23 tumor and 23 non-tumor gastric mucosa samples from advanced GC patients, and in AGS, MKN28 and MKN45 gastric cancer cell lines. Results showed a slight overexpression of PIK3CA, PIK3CB, AKT1, MTOR, RPS6KB1, EIF4EBP1 and EIF4E genes, and a slightly decreased PTEN and TSC1 expression. In AGS, MKN28 and MKN45 cells a significant gene overexpression of PIK3CA, PIK3CB, AKT1, MTOR, RPS6KB1 and EIF4E, and a significant repression of PTEN gene expression were observed. Immunoblotting showed that PI3K-β, AKT, p-AKT, PTEN, mTOR, p-mTOR, P70S6K1, p-P70S6K1, 4E-BP1, p-4E-BP1, eIF4E and p-eIF4E proteins were present in cell lines at different levels, confirming activation of this pathway in vitro. This is the first time this extensive panel of 9 genes within PI3K/AKT/mTOR pathway has been studied in GC to clarify the biological role of this pathway in GC and develop new strategies for this malignancy.
Literatur
1.
2.
Zurück zum Zitat Brenner H, Rothenbacher D, Arndt V (2009) Epidemiology of stomach cancer. Methods Mol Biol 472:467–477CrossRefPubMed Brenner H, Rothenbacher D, Arndt V (2009) Epidemiology of stomach cancer. Methods Mol Biol 472:467–477CrossRefPubMed
4.
5.
Zurück zum Zitat Zhang W (2014) TCGA divides gastric cancer into four molecular subtypes: implications for individualized therapeutics. Chin J Cancer 33:469–470PubMedPubMedCentral Zhang W (2014) TCGA divides gastric cancer into four molecular subtypes: implications for individualized therapeutics. Chin J Cancer 33:469–470PubMedPubMedCentral
6.
Zurück zum Zitat Al-Batran S-E, Ducreux M, Ohtsu A (2012) mTOR as a therapeutic target in patients with gastric cancer. Int J Cancer 130:491–496CrossRefPubMed Al-Batran S-E, Ducreux M, Ohtsu A (2012) mTOR as a therapeutic target in patients with gastric cancer. Int J Cancer 130:491–496CrossRefPubMed
7.
Zurück zum Zitat Fan Q-W, Weiss WA (2010) Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance. Curr Top Microbiol Immunol 347:279–296PubMedPubMedCentral Fan Q-W, Weiss WA (2010) Targeting the RTK-PI3K-mTOR axis in malignant glioma: overcoming resistance. Curr Top Microbiol Immunol 347:279–296PubMedPubMedCentral
8.
Zurück zum Zitat Matsuoka T, Yashiro M (2014) The role of PI3K/Akt/mTOR signaling in gastric carcinoma. Cancers (Basel) 6:1441–1463CrossRef Matsuoka T, Yashiro M (2014) The role of PI3K/Akt/mTOR signaling in gastric carcinoma. Cancers (Basel) 6:1441–1463CrossRef
9.
Zurück zum Zitat Yang W, Raufi A, Klempner SJ (2014) Targeted therapy for gastric cancer: molecular pathways and ongoing investigations. Biochim Biophys Acta 1846:232–237PubMed Yang W, Raufi A, Klempner SJ (2014) Targeted therapy for gastric cancer: molecular pathways and ongoing investigations. Biochim Biophys Acta 1846:232–237PubMed
10.
Zurück zum Zitat Morgensztern D, McLeod HL (2005) PI3K/Akt/mTOR pathway as a target for cancer therapy. Anti-Cancer Drugs 16:797–803CrossRefPubMed Morgensztern D, McLeod HL (2005) PI3K/Akt/mTOR pathway as a target for cancer therapy. Anti-Cancer Drugs 16:797–803CrossRefPubMed
11.
Zurück zum Zitat Caron E, Ghosh S, Matsuoka Y, Ashton-Beaucage D, Therrien M, et al. (2010) A comprehensive map of the mTOR signaling network. Mol Syst Biol 6:453CrossRefPubMedPubMedCentral Caron E, Ghosh S, Matsuoka Y, Ashton-Beaucage D, Therrien M, et al. (2010) A comprehensive map of the mTOR signaling network. Mol Syst Biol 6:453CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Polivka J, Janku F (2014) Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther 142:164–175CrossRefPubMed Polivka J, Janku F (2014) Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol Ther 142:164–175CrossRefPubMed
13.
Zurück zum Zitat Tapia O, Riquelme I, Leal P, Sandoval A, Aedo S, et al. (2014) The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch 465:25–33CrossRefPubMed Tapia O, Riquelme I, Leal P, Sandoval A, Aedo S, et al. (2014) The PI3K/AKT/mTOR pathway is activated in gastric cancer with potential prognostic and predictive significance. Virchows Arch 465:25–33CrossRefPubMed
14.
Zurück zum Zitat Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS, Workman P (2008) Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 8:393–412CrossRefPubMed Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS, Workman P (2008) Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 8:393–412CrossRefPubMed
15.
17.
Zurück zum Zitat Dreesen O, Brivanlou AH (2007) Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev 3:7–17CrossRefPubMed Dreesen O, Brivanlou AH (2007) Signaling pathways in cancer and embryonic stem cells. Stem Cell Rev 3:7–17CrossRefPubMed
18.
Zurück zum Zitat Xiao L, Wang YC, Li WS, Du Y (2009) The role of mTOR and phospho-p70S6K in pathogenesis and progression of gastric carcinomas: an immunohistochemical study on tissue microarray. J Exp Clin Cancer Res 28:152CrossRefPubMedPubMedCentral Xiao L, Wang YC, Li WS, Du Y (2009) The role of mTOR and phospho-p70S6K in pathogenesis and progression of gastric carcinomas: an immunohistochemical study on tissue microarray. J Exp Clin Cancer Res 28:152CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Chen H, Guan R, Lei Y, Chen J, Ge Q, et al. (2015) Lymphangiogenesis in gastric cancer regulated through Akt/mTOR-VEGF-C/VEGF-D axis. BMC Cancer 15:103CrossRefPubMedPubMedCentral Chen H, Guan R, Lei Y, Chen J, Ge Q, et al. (2015) Lymphangiogenesis in gastric cancer regulated through Akt/mTOR-VEGF-C/VEGF-D axis. BMC Cancer 15:103CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Greenfield LK, Jones NL (2013) Modulation of autophagy by helicobacter pylori and its role in gastric carcinogenesis. Trends Microbiol 21:602–612CrossRefPubMed Greenfield LK, Jones NL (2013) Modulation of autophagy by helicobacter pylori and its role in gastric carcinogenesis. Trends Microbiol 21:602–612CrossRefPubMed
21.
Zurück zum Zitat Liu JF, Zhou XK, Chen JH, Yi G, Chen HG, et al. (2010) Up-regulation of PIK3CA promotes metastasis in gastric carcinoma. World J Gastroenterol 16:4986–4991CrossRefPubMedPubMedCentral Liu JF, Zhou XK, Chen JH, Yi G, Chen HG, et al. (2010) Up-regulation of PIK3CA promotes metastasis in gastric carcinoma. World J Gastroenterol 16:4986–4991CrossRefPubMedPubMedCentral
22.
Zurück zum Zitat Ye B, Jiang L-L, Xu H-T, Zhou D-W, Li Z-S Expression of PI3K/AKT pathway in gastric cancer and its blockade suppresses tumor growth and metastasis. Int J Immunopathol Pharmacol 25:627–636 Ye B, Jiang L-L, Xu H-T, Zhou D-W, Li Z-S Expression of PI3K/AKT pathway in gastric cancer and its blockade suppresses tumor growth and metastasis. Int J Immunopathol Pharmacol 25:627–636
23.
Zurück zum Zitat Cinti C, Vindigni C, Zamparelli A, La Sala D, Epistolato MC, et al. (2008) Activated Akt as an indicator of prognosis in gastric cancer. Virchows Arch 453:449–455CrossRefPubMed Cinti C, Vindigni C, Zamparelli A, La Sala D, Epistolato MC, et al. (2008) Activated Akt as an indicator of prognosis in gastric cancer. Virchows Arch 453:449–455CrossRefPubMed
24.
Zurück zum Zitat Murayama T, Inokuchi M, Takagi Y, Yamada H, Kojima K, et al. (2009) Relation between outcomes and localisation of p-mTOR expression in gastric cancer. Br J Cancer 100:782–788CrossRefPubMedPubMedCentral Murayama T, Inokuchi M, Takagi Y, Yamada H, Kojima K, et al. (2009) Relation between outcomes and localisation of p-mTOR expression in gastric cancer. Br J Cancer 100:782–788CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Lang SA, Gaumann A, Koehl GE, Seidel U, Bataille F, et al. (2007) Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model. Int J Cancer 120:1803–1810CrossRefPubMed Lang SA, Gaumann A, Koehl GE, Seidel U, Bataille F, et al. (2007) Mammalian target of rapamycin is activated in human gastric cancer and serves as a target for therapy in an experimental model. Int J Cancer 120:1803–1810CrossRefPubMed
26.
Zurück zum Zitat Sun DF, jie ZY, XQ T, YX C, JY F (2014) Inhibition of mTOR signalling potentiates the effects of trichostatin a in human gastric cancer cell lines by promoting histone acetylation. Cell Biol Int 38:50–63CrossRefPubMed Sun DF, jie ZY, XQ T, YX C, JY F (2014) Inhibition of mTOR signalling potentiates the effects of trichostatin a in human gastric cancer cell lines by promoting histone acetylation. Cell Biol Int 38:50–63CrossRefPubMed
27.
Zurück zum Zitat Yang HY, Xue LY, Xing LX, Wang J, Wang JL, et al. (2013) Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma. Mol Med Rep 7:537–542PubMed Yang HY, Xue LY, Xing LX, Wang J, Wang JL, et al. (2013) Putative role of the mTOR/4E-BP1 signaling pathway in the carcinogenesis and progression of gastric cardiac adenocarcinoma. Mol Med Rep 7:537–542PubMed
28.
Zurück zum Zitat Fan S, Ramalingam SS, Kauh J, Xu Z, Khuri FR, Sun S-Y (2014) Phosphorylated eukaryotic translation initiation factor 4 (eIF4E) is elevated in human cancer tissues. Cancer Biol Ther 8:1463–1469CrossRef Fan S, Ramalingam SS, Kauh J, Xu Z, Khuri FR, Sun S-Y (2014) Phosphorylated eukaryotic translation initiation factor 4 (eIF4E) is elevated in human cancer tissues. Cancer Biol Ther 8:1463–1469CrossRef
29.
Zurück zum Zitat Liang S, Guo R, Zhang Z, Liu D, Xu H, et al. (2013) Upregulation of the eIF4E signaling pathway contributes to the progression of gastric cancer, and targeting eIF4E by perifosine inhibits cell growth. Oncol Rep 29:2422–2430PubMed Liang S, Guo R, Zhang Z, Liu D, Xu H, et al. (2013) Upregulation of the eIF4E signaling pathway contributes to the progression of gastric cancer, and targeting eIF4E by perifosine inhibits cell growth. Oncol Rep 29:2422–2430PubMed
30.
Zurück zum Zitat Chen C-N, Hsieh F-J, Cheng Y-M, Lee P-H, Chang K-J (2004) Expression of eukaryotic initiation factor 4E in gastric adenocarcinoma and its association with clinical outcome. J Surg Oncol 86:22–27CrossRefPubMed Chen C-N, Hsieh F-J, Cheng Y-M, Lee P-H, Chang K-J (2004) Expression of eukaryotic initiation factor 4E in gastric adenocarcinoma and its association with clinical outcome. J Surg Oncol 86:22–27CrossRefPubMed
31.
Zurück zum Zitat Wen Y-G, Wang Q, Zhou C-Z, Qiu G-Q, Peng Z-H, Tang H-M (2010) Mutation analysis of tumor suppressor gene PTEN in patients with gastric carcinomas and its impact on PI3K/AKT pathway. Oncol Rep 24:89–95PubMed Wen Y-G, Wang Q, Zhou C-Z, Qiu G-Q, Peng Z-H, Tang H-M (2010) Mutation analysis of tumor suppressor gene PTEN in patients with gastric carcinomas and its impact on PI3K/AKT pathway. Oncol Rep 24:89–95PubMed
32.
Zurück zum Zitat Kang Y-H, Lee HS, Kim WH (2002) Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Investig 82:285–291CrossRefPubMed Kang Y-H, Lee HS, Kim WH (2002) Promoter methylation and silencing of PTEN in gastric carcinoma. Lab Investig 82:285–291CrossRefPubMed
33.
Zurück zum Zitat Schwanhäusser B, Busse D, Li N, Dittmar G, Schuchhardt J, et al. (2011) Global quantification of mammalian gene expression control. Nature 473:337–342CrossRefPubMed Schwanhäusser B, Busse D, Li N, Dittmar G, Schuchhardt J, et al. (2011) Global quantification of mammalian gene expression control. Nature 473:337–342CrossRefPubMed
34.
Zurück zum Zitat The Cancer Genome Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202–209CrossRef The Cancer Genome Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202–209CrossRef
Metadaten
Titel
The Gene Expression Status of the PI3K/AKT/mTOR Pathway in Gastric Cancer Tissues and Cell Lines
verfasst von
Ismael Riquelme
Oscar Tapia
Jaime A. Espinoza
Pamela Leal
Kurt Buchegger
Alejandra Sandoval
Carolina Bizama
Juan Carlos Araya
Richard M. Peek
Juan Carlos Roa
Publikationsdatum
07.05.2016
Verlag
Springer Netherlands
Erschienen in
Pathology & Oncology Research / Ausgabe 4/2016
Print ISSN: 1219-4956
Elektronische ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-016-0066-5

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