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Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

The transcription factor FOXO4 is down-regulated and inhibits tumor proliferation and metastasis in gastric cancer

Authors: Linna Su, Xiangqiang Liu, Na Chai, Lifen Lv, Rui Wang, Xiaosa Li, Yongzhan Nie, Yongquan Shi, Daiming Fan

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

FOXO4, a member of the FOXO family of transcription factors, is currently the focus of intense study. Its role and function in gastric cancer have not been fully elucidated. The present study was aimed to investigate the expression profile of FOXO4 in gastric cancer and the effect of FOXO4 on cancer cell growth and metastasis.

Methods

Immunohistochemistry, Western blotting and qRT-PCR were performed to detect the FOXO4 expression in gastric cancer cells and tissues. Cell biological assays, subcutaneous tumorigenicity and tail vein metastatic assay in combination with lentivirus construction were performed to detect the impact of FOXO4 to gastric cancer in proliferation and metastasis in vitro and in vivo. Confocal and qRT-PCR were performed to explore the mechanisms.

Results

We found that the expression of FOXO4 was decreased significantly in most gastric cancer tissues and in various human gastric cancer cell lines. Up-regulating FOXO4 inhibited the growth and metastasis of gastric cancer cell lines in vitro and led to dramatic attenuation of tumor growth, and liver and lung metastasis in vivo, whereas down-regulating FOXO4 with specific siRNAs promoted the growth and metastasis of gastric cancer cell lines. Furthermore, we found that up-regulating FOXO4 could induce significant G1 arrest and S phase reduction and down-regulation of the expression of vimentin.

Conclusion

Our data suggest that loss of FOXO4 expression contributes to gastric cancer growth and metastasis, and it may serve as a potential therapeutic target for gastric cancer.
Appendix
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Literature
1.
go back to reference Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61 (2): 69-90. 10.3322/caac.20107.CrossRefPubMed Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin. 2011, 61 (2): 69-90. 10.3322/caac.20107.CrossRefPubMed
2.
go back to reference Jiang Y, Wang L, Gong W, Wei D, Le X, Yao J, Ajani J, Abbruzzese JL, Huang S, Xie K: A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer. Clin Exp Metastasis. 2004, 21 (8): 755-764.CrossRefPubMed Jiang Y, Wang L, Gong W, Wei D, Le X, Yao J, Ajani J, Abbruzzese JL, Huang S, Xie K: A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer. Clin Exp Metastasis. 2004, 21 (8): 755-764.CrossRefPubMed
3.
go back to reference Kajita Y, Kato T, Tamaki S, Furu M, Takahashi R, Nagayama S, Aoyama T, Nishiyama H, Nakamura E, Katagiri T, Nakamura Y, Ogawa O, Toguchida J: The transcription factor Sp3 regulates the expression of a metastasis-related marker of sarcoma, actin filament-associated protein 1-like 1 (AFAP1L1). PloS one. 2013, 8 (1): e49709-10.1371/journal.pone.0049709.CrossRefPubMedPubMedCentral Kajita Y, Kato T, Tamaki S, Furu M, Takahashi R, Nagayama S, Aoyama T, Nishiyama H, Nakamura E, Katagiri T, Nakamura Y, Ogawa O, Toguchida J: The transcription factor Sp3 regulates the expression of a metastasis-related marker of sarcoma, actin filament-associated protein 1-like 1 (AFAP1L1). PloS one. 2013, 8 (1): e49709-10.1371/journal.pone.0049709.CrossRefPubMedPubMedCentral
4.
go back to reference Zhang H, Meng F, Liu G, Zhang B, Zhu J, Wu F, Ethier SP, Miller F, Wu G: Forkhead transcription factor foxq1 promotes epithelial-mesenchymal transition and breast cancer metastasis. Cancer Res. 2011, 71 (4): 1292-1301. 10.1158/0008-5472.CAN-10-2825.CrossRefPubMedPubMedCentral Zhang H, Meng F, Liu G, Zhang B, Zhu J, Wu F, Ethier SP, Miller F, Wu G: Forkhead transcription factor foxq1 promotes epithelial-mesenchymal transition and breast cancer metastasis. Cancer Res. 2011, 71 (4): 1292-1301. 10.1158/0008-5472.CAN-10-2825.CrossRefPubMedPubMedCentral
5.
go back to reference Atreya I, Schimanski CC, Becker C, Wirtz S, Dornhoff H, Schnurer E, Berger MR, Galle PR, Herr W, Neurath MF: The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer. Gut. 2007, 56 (11): 1572-1578. 10.1136/gut.2006.117812.CrossRefPubMedPubMedCentral Atreya I, Schimanski CC, Becker C, Wirtz S, Dornhoff H, Schnurer E, Berger MR, Galle PR, Herr W, Neurath MF: The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer. Gut. 2007, 56 (11): 1572-1578. 10.1136/gut.2006.117812.CrossRefPubMedPubMedCentral
6.
go back to reference Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, Ferraro F, Mercier F, Singh H, Brumme KM, Acharya SS, Scholl C, Tothova Z, Attar EC, Frohling S, DePinho RA, Armstrong SA, Gilliland DG, Scadden DT: AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell. 2011, 146 (5): 697-708. 10.1016/j.cell.2011.07.032.CrossRefPubMed Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, Ferraro F, Mercier F, Singh H, Brumme KM, Acharya SS, Scholl C, Tothova Z, Attar EC, Frohling S, DePinho RA, Armstrong SA, Gilliland DG, Scadden DT: AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell. 2011, 146 (5): 697-708. 10.1016/j.cell.2011.07.032.CrossRefPubMed
7.
go back to reference Daitoku H, Sakamaki J, Fukamizu A: Regulation of FoxO transcription factors by acetylation and protein-protein interactions. Biochim Biophys Acta. 2011, 1813 (11): 1954-1960. 10.1016/j.bbamcr.2011.03.001.CrossRefPubMed Daitoku H, Sakamaki J, Fukamizu A: Regulation of FoxO transcription factors by acetylation and protein-protein interactions. Biochim Biophys Acta. 2011, 1813 (11): 1954-1960. 10.1016/j.bbamcr.2011.03.001.CrossRefPubMed
8.
go back to reference Maiese K, Chong ZZ, Shang YC: OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins. Trends Mol Med. 2008, 14 (5): 219-227. 10.1016/j.molmed.2008.03.002.CrossRefPubMedPubMedCentral Maiese K, Chong ZZ, Shang YC: OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins. Trends Mol Med. 2008, 14 (5): 219-227. 10.1016/j.molmed.2008.03.002.CrossRefPubMedPubMedCentral
9.
go back to reference van der Vos KE, Coffer PJ: FOXO-binding partners: it takes two to tango. Oncogene. 2008, 27 (16): 2289-2299. 10.1038/onc.2008.22.CrossRefPubMed van der Vos KE, Coffer PJ: FOXO-binding partners: it takes two to tango. Oncogene. 2008, 27 (16): 2289-2299. 10.1038/onc.2008.22.CrossRefPubMed
10.
go back to reference Watroba M, Maslinska D, Maslinski S: Current overview of functions of FoxO proteins, with special regards to cellular homeostasis, cell response to stress, as well as inflammation and aging. Adv Med Sci. 2012, 57 (2): 183-195. 10.2478/v10039-012-0039-1.CrossRefPubMed Watroba M, Maslinska D, Maslinski S: Current overview of functions of FoxO proteins, with special regards to cellular homeostasis, cell response to stress, as well as inflammation and aging. Adv Med Sci. 2012, 57 (2): 183-195. 10.2478/v10039-012-0039-1.CrossRefPubMed
11.
go back to reference Zhu J, Mounzih K, Chehab EF, Mitro N, Saez E, Chehab FF: Effects of FoxO4 overexpression on cholesterol biosynthesis, triacylglycerol accumulation, and glucose uptake. J Lipid Res. 2010, 51 (6): 1312-1324. 10.1194/jlr.M001586.CrossRefPubMedPubMedCentral Zhu J, Mounzih K, Chehab EF, Mitro N, Saez E, Chehab FF: Effects of FoxO4 overexpression on cholesterol biosynthesis, triacylglycerol accumulation, and glucose uptake. J Lipid Res. 2010, 51 (6): 1312-1324. 10.1194/jlr.M001586.CrossRefPubMedPubMedCentral
12.
go back to reference Liu X, Zhang Z, Sun L, Chai N, Tang S, Jin J, Hu H, Nie Y, Wang X, Wu K, Jin H, Fan D: MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4. Carcinogenesis. 2011, 32 (12): 1798-1805. 10.1093/carcin/bgr213.CrossRefPubMed Liu X, Zhang Z, Sun L, Chai N, Tang S, Jin J, Hu H, Nie Y, Wang X, Wu K, Jin H, Fan D: MicroRNA-499-5p promotes cellular invasion and tumor metastasis in colorectal cancer by targeting FOXO4 and PDCD4. Carcinogenesis. 2011, 32 (12): 1798-1805. 10.1093/carcin/bgr213.CrossRefPubMed
13.
go back to reference Zhang Y, Gan B, Liu D, Paik JH: FoxO family members in cancer. Cancer Biol Ther. 2011, 12 (4): 253-259. 10.4161/cbt.12.4.15954.CrossRefPubMed Zhang Y, Gan B, Liu D, Paik JH: FoxO family members in cancer. Cancer Biol Ther. 2011, 12 (4): 253-259. 10.4161/cbt.12.4.15954.CrossRefPubMed
14.
go back to reference Zhang X, Tang N, Hadden TJ, Rishi AK: Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011, 1813 (11): 1978-1986. 10.1016/j.bbamcr.2011.03.010.CrossRefPubMed Zhang X, Tang N, Hadden TJ, Rishi AK: Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta. 2011, 1813 (11): 1978-1986. 10.1016/j.bbamcr.2011.03.010.CrossRefPubMed
15.
go back to reference Kleindorp R, Flachsbart F, Puca AA, Malovini A, Schreiber S, Nebel A: Candidate gene study of FOXO1, FOXO4, and FOXO6 reveals no association with human longevity in Germans. Aging Cell. 2011, 10 (4): 622-628. 10.1111/j.1474-9726.2011.00698.x.CrossRefPubMed Kleindorp R, Flachsbart F, Puca AA, Malovini A, Schreiber S, Nebel A: Candidate gene study of FOXO1, FOXO4, and FOXO6 reveals no association with human longevity in Germans. Aging Cell. 2011, 10 (4): 622-628. 10.1111/j.1474-9726.2011.00698.x.CrossRefPubMed
16.
go back to reference Iyer S, Ambrogini E, Bartell SM, Han L, Roberson PK, de Cabo R, Jilka RL, Weinstein RS, O'Brien CA, Manolagas SC, Almeida M: FOXOs attenuate bone formation by suppressing Wnt signaling. J Clin Invest. 2013, 123 (8): 3409-3419. 10.1172/JCI68049.CrossRefPubMedPubMedCentral Iyer S, Ambrogini E, Bartell SM, Han L, Roberson PK, de Cabo R, Jilka RL, Weinstein RS, O'Brien CA, Manolagas SC, Almeida M: FOXOs attenuate bone formation by suppressing Wnt signaling. J Clin Invest. 2013, 123 (8): 3409-3419. 10.1172/JCI68049.CrossRefPubMedPubMedCentral
17.
go back to reference Bullock MD, Sayan AE, Packham GK, Mirnezami AH: MicroRNAs: critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression. Biol Cell. 2012, 104 (1): 3-12. 10.1111/boc.201100115.CrossRefPubMed Bullock MD, Sayan AE, Packham GK, Mirnezami AH: MicroRNAs: critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression. Biol Cell. 2012, 104 (1): 3-12. 10.1111/boc.201100115.CrossRefPubMed
18.
go back to reference Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Canc. 2002, 2 (6): 442-454. 10.1038/nrc822.CrossRef Thiery JP: Epithelial-mesenchymal transitions in tumour progression. Nat Rev Canc. 2002, 2 (6): 442-454. 10.1038/nrc822.CrossRef
19.
go back to reference Spaderna S, Schmalhofer O, Hlubek F, Berx G, Eger A, Merkel S, Jung A, Kirchner T, Brabletz T: A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology. 2006, 131 (3): 830-840. 10.1053/j.gastro.2006.06.016.CrossRefPubMed Spaderna S, Schmalhofer O, Hlubek F, Berx G, Eger A, Merkel S, Jung A, Kirchner T, Brabletz T: A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology. 2006, 131 (3): 830-840. 10.1053/j.gastro.2006.06.016.CrossRefPubMed
Metadata
Title
The transcription factor FOXO4 is down-regulated and inhibits tumor proliferation and metastasis in gastric cancer
Authors
Linna Su
Xiangqiang Liu
Na Chai
Lifen Lv
Rui Wang
Xiaosa Li
Yongzhan Nie
Yongquan Shi
Daiming Fan
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-378

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