nach oben

Erschienen in:

01.01.2015 | Original Article

The Transcription Factor FOXA2 Suppresses Gastric Tumorigenesis In Vitro and In Vivo

verfasst von: Chang-Peng Zhu, Jian Wang, Bin Shi, Ping-Fang Hu, Bei-Fang Ning, Qing Zhang, Fei Chen, Wan-Sheng Chen, Xin Zhang, Wei-Fen Xie

Erschienen in: Digestive Diseases and Sciences | Ausgabe 1/2015

Einloggen, um Zugang zu erhalten

Abstract

Background and Aims

The transcription factor forkhead box A2 (FOXA2) plays a central role in the development of endoderm-derived organs. It has been reported that FOXA2 acts as a suppressor in many kinds of tumor. However, little is known about the role of FOXA2 in gastric cancer.

Methods

The expression of FOXA2 in gastric cancer tissue samples from 89 patients was assessed by immunohistochemistry, and the clinicopathological characteristics of the samples were analyzed. The human gastric cancer cell line, BGC-823, was used to investigate the effects of FOXA2 in gastric cancer in vitro and in vivo and the potential mechanism involved was explored.

Results

FOXA2 expression in human gastric cancer cell lines and human gastric cancer tissues was lower compared with the normal gastric epithelium cell line GES1 and normal adult gastric tissues, respectively. Patients with high FOXA2 expression level had longer 5-year overall survival than those with low FOXA2 expression level. FOXA2 markedly inhibited growth of BGC-823 cells accompanied with the cell cycle arrest and apoptosis. Infection of BGC-823 cells by FOXA2 lentivirus resulted in reduced cell tumorigenesis in vitro and in vivo. Moreover, expression of Mucin 5AC was up-regulated along with increased expression of exogenous FOXA2 in BGC-823 cells; in contrast, dedifferentiation markers, BMI, CD54 and CD24, were down-regulated.

Conclusions

These results suggest that FOXA2 induces the differentiation of gastric cancer and highlight FOXA2 as a novel therapeutic target and prognostic marker for human gastric cancer.

Nur mit Berechtigung zugänglich

Danaei G, Vander Hoor S, Lopez AD, Murray CJ, Ezzati M. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet. 2005;366:1784–1793.PubMedCrossRef

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29.PubMedCrossRef

Schrem H, Klempnauer J, Borlak J. Liver-enriched transcription factors in liver function and development. Part I: the hepatocyte nuclear factor network and liver-specific gene expression. Pharmacol Rev. 2002;54:129–158.PubMedCrossRef

Xu L, Hui L, Wang S, et al. Expression profiling suggested a regulatory role of liver-enriched transcription factors in human hepatocellular carcinoma. Cancer Res. 2001;61:3176–3181.PubMed

Yin C, Lin Y, Zhang X, et al. Differentiation therapy of hepatocellular carcinoma in mice with recombinant adenovirus carrying hepatocyte nuclear factor-4α gene. Hepatology. 2008;48:1528–1539.PubMedCrossRef

Zeng X, Lin Y, Yin C, et al. Recombinant adenovirus carrying the hepatocyte nuclear factor-1alpha gene inhibits hepatocellular carcinoma xenograft growth in mice. Hepatology. 2011;54:2036–2047.PubMedCrossRef

Friedman J, Kaestner K. The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci. 2006;63:2317–2328.PubMedCrossRef

Lee CS, Sund NJ, Behr R, Herrera PL, Kaestner KH. Foxa2 is required for the differentiation of pancreatic α-cells. Dev Biol. 2005;278:484–495.PubMedCrossRef

Lee CS, Friedman JR, Fulmer JT, Kaestner KH. The initiation of liver development is dependent on Foxa transcription factors. Nature. 2005;435:944–947.PubMedCrossRef

10.

Wan H, Kaestner KH, Ang SL, et al. Foxa2 regulates alveolarization and goblet cell hyperplasia. Development. 2004;131:953–964.PubMedCrossRef

11.

Wang H, Gauthier BR, Hagenfeldt-Johansson KA, Iezzi M, Wollheim CB. Foxa2 (HNF3β) controls multiple genes implicated in metabolism-secretion coupling of glucose-induced insulin release. J Biol Chem. 2002;277:17564–17570.PubMedCrossRef

12.

Wolfrum C, Asilmaz E, Luca E, Friedman JM, Stoffel M. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature. 2004;432:1027–1032.PubMedCrossRef

13.

Halmos B, Bassères DS, Monti S, et al. A transcriptional profiling study of CCAAT/enhancer binding protein targets identifies hepatocyte nuclear factor 3β as a novel tumor suppressor in lung cancer. Cancer Res. 2004;64:4137–4147.PubMedCrossRef

14.

Miyamoto K, Fukutomi T, Akashi-Tanaka S, et al. Identification of 20 genes aberrantly methylated in human breast cancers. Int J Cancer. 2005;116:407–414.PubMedCrossRef

15.

Akagi T, Luong Q, Gui D, et al. Induction of sodium iodide symporter gene and molecular characterisation of HNF3β/FoxA2, TTF-1 and C/EBPβ in thyroid carcinoma cells. Br J Cancer. 2008;99:781–788.PubMedCentralPubMedCrossRef

16.

Tang Y, Shu G, Yuan X, Jing N, Song J. FOXA2 functions as a suppressor of tumor metastasis by inhibition of epithelial-to-mesenchymal transition in human lung cancers. Cell Res. 2010;21:316–326.PubMedCentralPubMedCrossRef

17.

Song Y, Washington MK, Crawford HC. Loss of FOXA1/2 is essential for the epithelial-to-mesenchymal transition in pancreatic cancer. Cancer Res. 2010;70:2115–2125.PubMedCentralPubMedCrossRef

18.

Liu M, Lee DF, Chen CT, et al. IKKα activation of NOTCH links tumorigenesis via FOXA2 suppression. Mol Cell. 2012;45:171–184.PubMedCentralPubMedCrossRef

19.

Li Z, Tuteja G, Schug J, Kaestner KH. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell. 2012;148:72–83.PubMedCentralPubMedCrossRef

20.

Sekiya T, Muthurajan UM, Luger K, Tulin AV, Zaret KS. Nucleosome-binding affinity as a primary determinant of the nuclear mobility of the pioneer transcription factor FoxA. Genes Dev. 2009;23:804–809.PubMedCentralPubMedCrossRef

21.

Cereghini S. Liver-enriched transcription factors and hepatocyte differentiation. FASEB J. 1996;10:267–282.PubMed

22.

Montgomery RK, Mulberg AE, Grand RJ. Development of the human gastrointestinal tract: twenty years of progress. Gastroenterology. 1999;116:702–731.PubMedCrossRef

23.

Tenen DG. Disruption of differentiation in human cancer: AML shows the way. Nat Rev Cancer. 2003;3:89–101.PubMedCrossRef

24.

Hatziapostolou M, Polytarchou C, Aggelidou E, et al. An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell. 2011;147:1233–1247.PubMedCentralPubMedCrossRef

25.

Richmond CA, Breault DT. Regulation of gene expression in the intestinal epithelium. Prog Mol Biol Transl Sci. 2010;96:207.PubMedCentralPubMedCrossRef

26.

McGuckin MA, Lindén SK, Sutton P, Florin TH. Mucin dynamics and enteric pathogens. Nat Rev Microbiol. 2011;9:265–278.PubMedCrossRef

27.

Buisine M, Devisme L, Savidge T, et al. Mucin gene expression in human embryonic and fetal intestine. Gut. 1998;43:519–524.PubMedCentralPubMedCrossRef

28.

Buisine MP, Devisme L, Maunoury V, et al. Developmental mucin gene expression in the gastroduodenal tract and accessory digestive glands. I. Stomach: a relationship to gastric carcinoma. J Histochem Cytochem. 2000;48:1657–1665.PubMedCrossRef

29.

Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol. 2004;51:1–28.PubMedCrossRef

30.

Ning BF, Ding J, Yin C, et al. Hepatocyte nuclear factor 4α suppresses the development of hepatocellular carcinoma. Cancer Res. 2010;70:7640–7651.PubMedCrossRef

Titel: The Transcription Factor FOXA2 Suppresses Gastric Tumorigenesis In Vitro and In Vivo
verfasst von: Chang-Peng Zhu
Jian Wang
Bin Shi
Ping-Fang Hu
Bei-Fang Ning
Qing Zhang
Fei Chen
Wan-Sheng Chen
Xin Zhang
Wei-Fen Xie
Publikationsdatum: 01.01.2015
Verlag: Springer US
Erschienen in: Digestive Diseases and Sciences / Ausgabe 1/2015
Print ISSN: 0163-2116
Elektronische ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-014-3290-4

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

16.04.2024 | Spondylitis ankylosans | Nachrichten

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

The Transcription Factor FOXA2 Suppresses Gastric Tumorigenesis In Vitro and In Vivo

Abstract

Background and Aims

Methods

Results

Conclusions

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Sind Betablocker auch für ältere herzschwache Personen nützlich?

Kein Abstrich bei chronischen Wunden ohne Entzündungszeichen!

Manche Gestagene können das Risiko für Meningeome erhöhen

Update Innere Medizin

Springer Medizin

Abstract

Background and Aims

Methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 1/2015

Fusobacterium Detected in Colonic Biopsy and Clinicopathological Features of Ulcerative Colitis in Japan

Transenteral Bowel Preparation for Colonoscopy Is More Comfortable than the Traditional Method with No Inferiority in Efficacy

Once-Daily Omeprazole/Sodium Bicarbonate Heals Severe Refractory Reflux Esophagitis with Morning or Nighttime Dosing

Krüpple-Like Factor 5 Is Required for Proper Maintenance of Adult Intestinal Crypt Cellular Proliferation

Low SVR Rates in Clinical Practice for Treating Genotype 1 Chronic Hepatitis C with Protease Inhibitors Boceprevir and Telaprevir

Bowel Preparation: Is Endoscopic Administration Worth the Extra Risk?

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Sind Betablocker auch für ältere herzschwache Personen nützlich?

Kein Abstrich bei chronischen Wunden ohne Entzündungszeichen!

Manche Gestagene können das Risiko für Meningeome erhöhen

Update Innere Medizin