Gastrointestinal Factor GDDR Attenuates Epithelial-Mesenchymal Transition in Gastric Cancer Via Inhibiting AKT Signal

Overview

Journal Dig Dis Sci

Specialty Gastroenterology

Date 2016 Mar 28

PMID 27017226

Authors

Cheng Fang

Ziqiang Zhang

ChaoXu Liu

Gang Wang

Fei Wang

Zhanwei Zhao

Wenhui Li

Jin Hua

Jianbo Shuang

Jianjun Du

Affiliations

Soon will be listed here.

Abstract

Background: The gastric dramatic down-related gene (GDDR) is an abundantly expressed secretory protein in normal gastric epithelia, while its expression is distinctly decreased in gastric cancer. However, the role of GDDR in gastric cancer remains poorly understood.

Aims: This study aims to detect the expression and clinical significance of GDDR in gastric cancer and investigate its effects on epithelial-mesenchymal transition.

Methods: The expression of GDDR in gastric cancer was examined by immunohistochemistry, immunoblotting, and Western blotting. The relationships between GDDR expression and clinicopathological factors were evaluated. The effects of GDDR on epithelial-mesenchymal transition of gastric cancer cells were investigated in vitro.

Results: GDDR was absent in gastric cancer tissue or dramatically downregulated in gastric cancer cell lines. Loss of GDDR expression in gastric cancer was strongly correlated with clinicopathological factors, such as tumor differentiation (p = 0.037), T stage (p < 0.001), lymph node metastasis (p = 0.008) and TNM stage (p < 0.001). Patients with decreased GDDR expression presented shortened overall survival (p = 0.033). Functional studies demonstrated that GDDR elevation augmented cell-cell adhesion and suppressed cell motility, concomitant with increased expression of E-cadherin and decreased expression of β-catenin and vimentin. Conversely, GDDR depletion increased cell motility, concomitant with decreased expression of E-cadherin and increased expression of β-catenin and vimentin. Moreover, GDDR had an inhibitory effect on PI3K/Akt signaling pathway.

Conclusions: Our findings suggested that GDDR expression was significantly associated with the progression of gastric cancer and GDDR may function as a tumor suppressor via inhibiting the epithelial-mesenchymal transition.

References

Shimizu T, Marusawa H, Watanabe N, Chiba T . Molecular Pathogenesis of Helicobacter pylori-Related Gastric Cancer. Gastroenterol Clin North Am. 2015; 44(3):625-38. DOI: 10.1016/j.gtc.2015.05.011. View

Okholm C, Svendsen L, Achiam M . Status and prognosis of lymph node metastasis in patients with cardia cancer - a systematic review. Surg Oncol. 2014; 23(3):140-6. DOI: 10.1016/j.suronc.2014.06.001. View

Moss S, Lee J, Sabo E, Rubin A, Rommel J, Westley B . Decreased expression of gastrokine 1 and the trefoil factor interacting protein TFIZ1/GKN2 in gastric cancer: influence of tumor histology and relationship to prognosis. Clin Cancer Res. 2008; 14(13):4161-7. PMC: 2572195. DOI: 10.1158/1078-0432.CCR-07-4381. View

Chu G, Qi S, Yang G, Dou K, Du J, Lu Z . Gastrointestinal tract specific gene GDDR inhibits the progression of gastric cancer in a TFF1 dependent manner. Mol Cell Biochem. 2011; 359(1-2):369-74. DOI: 10.1007/s11010-011-1030-z. View

Baus-Loncar M, Lubka M, Pusch C, Otto W, Poulsom R, Blin N . Cytokine regulation of the trefoil factor family binding protein GKN2 (GDDR/TFIZ1/blottin) in human gastrointestinal epithelial cells. Cell Physiol Biochem. 2007; 20(1-4):193-204. DOI: 10.1159/000104166. View

Ishaq S, Nunn L . Helicobacter pylori and gastric cancer: a state of the art review. Gastroenterol Hepatol Bed Bench. 2015; 8(Suppl 1):S6-S14. PMC: 4495426. View

Shi L, Wang H, Wang F, Feng M, Wang M, Guan W . Effects of gastrokine‑2 expression on gastric cancer cell apoptosis by activation of extrinsic apoptotic pathways. Mol Med Rep. 2014; 10(6):2898-904. PMC: 4227429. DOI: 10.3892/mmr.2014.2603. View

Valastyan S, Weinberg R . Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011; 147(2):275-92. PMC: 3261217. DOI: 10.1016/j.cell.2011.09.024. View

Li M, Feurino L, Li F, Wang H, Zhai Q, Fisher W . Thymosinalpha1 stimulates cell proliferation by activating ERK1/2, JNK, and increasing cytokine secretion in human pancreatic cancer cells. Cancer Lett. 2006; 248(1):58-67. DOI: 10.1016/j.canlet.2006.05.019. View

10.

Resnick M, Sabo E, Meitner P, Kim S, Cho Y, Kim H . Global analysis of the human gastric epithelial transcriptome altered by Helicobacter pylori eradication in vivo. Gut. 2006; 55(12):1717-24. PMC: 1856477. DOI: 10.1136/gut.2006.095646. View

11.

Kumar N, Afeyan R, Sheppard S, Harms B, Lauffenburger D . Quantitative analysis of Akt phosphorylation and activity in response to EGF and insulin treatment. Biochem Biophys Res Commun. 2007; 354(1):14-20. PMC: 2820294. DOI: 10.1016/j.bbrc.2006.12.188. View

12.

Menheniott T, Peterson A, OConnor L, Lee K, Kalantzis A, Kondova I . A novel gastrokine, Gkn3, marks gastric atrophy and shows evidence of adaptive gene loss in humans. Gastroenterology. 2010; 138(5):1823-35. DOI: 10.1053/j.gastro.2010.01.050. View

13.

Ebule I, Longdoh A, Paloheimo I . Helicobacter pylori infection and atrophic gastritis. Afr Health Sci. 2013; 13(1):112-7. PMC: 3645097. DOI: 10.4314/ahs.v13i1.15. View

14.

Du J, Dou K, Peng S, Wang W, Wang Z, Xiao H . [Down-regulated full-length novel gene GDDR and its effect on gastric cancer]. Zhonghua Yi Xue Za Zhi. 2003; 83(13):1166-8. View

15.

Suman S, Kurisetty V, Das T, Vadodkar A, Ramos G, Lakshmanaswamy R . Activation of AKT signaling promotes epithelial-mesenchymal transition and tumor growth in colorectal cancer cells. Mol Carcinog. 2013; 53 Suppl 1:E151-60. DOI: 10.1002/mc.22076. View

16.

Figueiredo C, Garcia-Gonzalez M, Machado J . Molecular pathogenesis of gastric cancer. Helicobacter. 2013; 18 Suppl 1:28-33. DOI: 10.1111/hel.12083. View

17.

Chen R, Yang Q, Lee J . BMK1 kinase suppresses epithelial-mesenchymal transition through the Akt/GSK3β signaling pathway. Cancer Res. 2012; 72(6):1579-87. PMC: 3306490. DOI: 10.1158/0008-5472.CAN-11-2055. View

18.

Liao G, Wang M, Ou Y, Zhao Y . IGF-1-induced epithelial-mesenchymal transition in MCF-7 cells is mediated by MUC1. Cell Signal. 2014; 26(10):2131-7. DOI: 10.1016/j.cellsig.2014.06.004. View

19.

Sasaki T, Kuniyasu H . Significance of AKT in gastric cancer (Review). Int J Oncol. 2014; 45(6):2187-92. DOI: 10.3892/ijo.2014.2678. View

20.

Zhang B, Yin C, Li H, Shi L, Liu N, Sun Y . Nir1 promotes invasion of breast cancer cells by binding to chemokine (C-C motif) ligand 18 through the PI3K/Akt/GSK3β/Snail signalling pathway. Eur J Cancer. 2013; 49(18):3900-13. DOI: 10.1016/j.ejca.2013.07.146. View