PTEN expression and suppression of proliferation are associated with Cdx2 overexpression in gastric cancer cells

Bai,Zhi-Gang; Ye,Ying-Jiang; Shen,Dan-Hua; Lu,You-Yong; Zhang,Zhong-Tao; Wang,Shan

doi:10.3892/ijo.2013.1875

PTEN expression and suppression of proliferation are associated with Cdx2 overexpression in gastric cancer cells

Authors:
- Zhi-Gang Bai
- Ying-Jiang Ye
- Dan-Hua Shen
- You-Yong Lu
- Zhong-Tao Zhang
- Shan Wang
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Affiliations: Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China, Department of Gastroenterological Surgery, Surgical Oncology Laboratory, Peking University People's Hospital, Beijing, P.R. China, Department of Pathology, Peking University People's Hospital, Beijing, P.R. China, Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University School of Oncology, Beijing Cancer Hospital/Institute, Beijing, P.R. China
Published online on: March 28, 2013 https://doi.org/10.3892/ijo.2013.1875
Pages: 1682-1691

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Abstract

The prognosis of gastric cancer (GC) is associated with Cdx2 and nuclear PTEN coexpression. This study aimed to determine the expression patterns of Cdx2 and PTEN in various GC tissues and cell lines to identify their relationship in GC. Immunohistochemistry was undertaken to assess the expression patterns of Cdx2 and PTEN in paraffin-embedded specimens of 228 GC patients who had undergone radical D2 gastrostomy with long-term follow-up. Cell growth and tumorigenicity were analyzed in the BGC823 cells with exogenous Cdx2 and any changes in the associated signaling pathways were interpreted in exogenous cdx2 expression and cdx2 knockdown. Cdx2 was found in the nuclei of GC cells in 43.4% (99/228) of the paraffin-embedded biopsies. A higher expression of nuclear PTEN was observed in 36.4% (83/228). Coexpression of Cdx2 and nuclear PTEN was detected in GC tumors (59/228, 25.9%) which correlated with the prognosis of advanced GC patients (p<0.001). The expression levels of Cdx2 and PTEN were variable in the different GC cell lines. However, the trends were similar between PTEN and Cdx2 in GC tissues and cell lines. High expression of Cdx2 and PTEN significantly reduced tumorigenicity in BGC823 cells compared with the empty vector control. Exogenous expression of Cdx2 triggered the upregulation of PTEN expression and decreased PI3K and pAkt expression and vice versa. The coexpression levels of PTEN and Cdx2 in GC tumors correlated with prognosis in GC patients. Cdx2 may play a role in the upregulation of PTEN by triggering PI3K/Akt inactivation in GC cells.

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1.	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar
2.	Peek RM Jr and Blaser MJ: Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nature reviews Cancer. 2:28–37. 2002. View Article : Google Scholar
3.	Lauren P: The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification Acta Pathol Microbiol Scand. 64:31–49. 1965.PubMed/NCBI
4.	Correa P: Human gastric carcinogenesis: a multistep and multifactorial process - First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 52:6735–6740. 1992.
5.	Barros R, Freund J-N, David L and Almeida R: Gastric intestinal metaplasia revisited: function and regulation of CDX2. Trends Mol Med. 18:555–563. 2012. View Article : Google Scholar : PubMed/NCBI
6.	Barros R, Camilo V, Pereira B, Freund JN, David L and Almeida R: Pathophysiology of intestinal metaplasia of the stomach: emphasis on CDX2 regulation. Biochem Soc Trans. 38:358–363. 2010. View Article : Google Scholar : PubMed/NCBI
7.	Stairs DB, Kong J and Lynch JP: Chapter 10 - Cdx genes, inflammation, and the pathogenesis of intestinal metaplasia. In Progress in Molecular Biology and Translational Science. 96. Klaus HK: Academic Press; Philadelphia: pp. 231–270. 2010
8.	Qin R, Wang NN, Chu J and Wang X: Expression and significance of homeodomain protein Cdx2 in gastric carcinoma and precancerous lesions. World J Gastroenterol. 18:3296–3302. 2012.PubMed/NCBI
9.	Silberg DG, Sullivan J, Kang E, et al: Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology. 122:689–696. 2002. View Article : Google Scholar : PubMed/NCBI
10.	Mutoh H, Sakurai S, Satoh K, et al: Development of gastric carcinoma from intestinal metaplasia in Cdx2-transgenic mice. Cancer Res. 64:7740–7747. 2004. View Article : Google Scholar : PubMed/NCBI
11.	Seno H, Oshima M, Taniguchi MA, et al: CDX2 expression in the stomach with intestinal metaplasia and intestinal-type cancer: Prognostic implications. Int J Oncol. 21:769–774. 2002.PubMed/NCBI
12.	Mizoshita T, Tsukamoto T, Nakanishi H, et al: Expression of Cdx2 and the phenotype of advanced gastric cancers: relationship with prognosis. J Cancer Res Clin Oncol. 129:727–734. 2003. View Article : Google Scholar : PubMed/NCBI
13.	Fan Z, Li J, Dong B and Huang X: Expression of Cdx2 and hepatocyte antigen in gastric carcinoma: correlation with histologic type and implications for prognosis. Clin Cancer. 11:6162–6170. 2005. View Article : Google Scholar : PubMed/NCBI
14.	Roessler K, Mönig SP, Schneider PM, et al: Co-expression of CDX2 and MUC2 in gastric carcinomas: correlations with clinicopathological parameters and prognosis. World J Gastroenterol. 11:3182–3188. 2005. View Article : Google Scholar : PubMed/NCBI
15.	Gil A, Andrés-Pons A, Fernández E, et al: Nuclear localization of PTEN by a Ran-dependent mechanism enhances apoptosis: involvement of an N-terminal nuclear localization domain and multiple nuclear exclusion motifs. Mol Biol Cell. 17:4002–4013. 2006. View Article : Google Scholar
16.	Sansal I and Sellers WR: The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 22:2954–2963. 2004. View Article : Google Scholar : PubMed/NCBI
17.	Tamura M, Gu J, Matsumoto K, Aota S, Parsons R and Yamada KM: Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science. 280:1614–1617. 1998. View Article : Google Scholar : PubMed/NCBI
18.	Shen WH, Balajee AS, Wang J, et al: Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell. 128:157–170. 2007. View Article : Google Scholar : PubMed/NCBI
19.	Bai Z, Ye Y, Chen D, et al: Homeoprotein Cdx2 and nuclear PTEN expression profiles are related to gastric cancer prognosis. APMIS. 115:1383–1390. 2007. View Article : Google Scholar : PubMed/NCBI
20.	Kim S, Domon-Dell C, Wang Q, et al: PTEN and TNF-alpha regulation of the intestinal-specific Cdx-2 homeobox gene through a PI3K, PKB/Akt, and NF-kappaB-dependent pathway. Gastroenterology. 123:1163–1178. 2002. View Article : Google Scholar : PubMed/NCBI
21.	Hinoi T, Gesina G, Akyol A, et al: CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium. Gastroenterology. 128:946–961. 2005. View Article : Google Scholar : PubMed/NCBI
22.	Yuasa Y: Control of gut differentiation and intestinal-type gastric carcinogenesis. Nature reviews. Cancer. 3:592–600. 2003. View Article : Google Scholar : PubMed/NCBI
23.	Xu Y, Zhang J, Liu QS and Dong WG: Knockdown of liver-intestine cadherin decreases BGC823 cell invasiveness and metastasis in vivo. World J Gastroenterol. 18:3129–3137. 2012.PubMed/NCBI
24.	Wu T, Li JY and Lu SX: Isolation and characterization of side population cells in human gastric cancer cell line BGC-823. Zhonghua Zhong Liu Za Zhi. 34:264–268. 2012.In Chinese.
25.	Dang LH, Chen F, Knock SA, et al: CDX2 does not suppress tumorigenicity in the human gastric cancer cell line MKN45. Oncogene. 25:2048–2059. 2006. View Article : Google Scholar : PubMed/NCBI
26.	Wrighton KH: Tumour suppressors: role of nuclear PTEN revealed. Nature reviews Cancer. 11:154. 2011. View Article : Google Scholar : PubMed/NCBI
27.	Pereira B, Oliveira C, David L and Almeida R: CDX2 promoter methylation is not associated with mRNA expression. Int J Cancer. 125:1739–1742. 2009. View Article : Google Scholar : PubMed/NCBI