Global transcriptome‑wide analysis of the function of GDDR in acute gastric lesions

Zhang,Ziqiang; Zhu,Jie; Dong,Yuanqiang; Xu,Hongyuan; Jiang,Tao; Li,Wenshuai; Xu,Diannan; Shi,Liubin; Yu,Jianghong; Zhang,Jun; Du,Jianjun

doi:10.3892/mmr.2017.7687

Global transcriptome‑wide analysis of the function of GDDR in acute gastric lesions

Authors:
- Ziqiang Zhang
- Jie Zhu
- Yuanqiang Dong
- Hongyuan Xu
- Tao Jiang
- Wenshuai Li
- Diannan Xu
- Liubin Shi
- Jianghong Yu
- Jun Zhang
- Jianjun Du
View Affiliations

Affiliations: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China, Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai 200040, P.R. China
Published online on: October 2, 2017 https://doi.org/10.3892/mmr.2017.7687
Pages: 8673-8684
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Acute gastric lesions induced by stress are frequent occurrences in medical establishments. The gastric dramatic downrelated gene (GDDR) is a secreted protein, which is abundantly expressed in normal gastric epithelia and is significantly decreased in gastric cancer. In our previous study, it was found that GDDR aggravated stress‑induced acute gastric lesions. However, the role of GDDR in acute gastric lesions remains to be fully elucidated. In the present study, RNA sequencing was performed in order to examine the gene expression profile regulated by GDDR in acute gastric lesions. The dataset comprised four stomach samples from wild-type (WT) mice and four stomach samples from GDDR‑knockout mice. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to analyze the differentially-expressed genes (DEGs). Weighted correlation network analysis was used to identify clusters of highly correlated genes. Cytoscape was used to construct a protein‑protein interaction network (PPI) of the DEGs. Based on the GO analysis, the upregulated DEGs were distinctly enriched in muscle contraction and response to wounding; and the downregulated DEGs were significantly enriched in the regulation of nitrogen compound metabolic process and regulation of RNA metabolic process. The results of the KEGG pathway analysis showed that the upregulated DEGs were enriched in ECM‑receptor interaction and the signaling pathway of cGMP‑PKG, and the downregulated DEGs were enriched in the renin‑angiotensin system and glycerolipid metabolism. The co‑expression network revealed a group of genes, which were associated with increased wound healing in the WT mice. Significant pathways were identified through the PPI network, including negative regulation of the signaling pathway of glucocorticoid receptor, regulation of cellular stress response, and regulation of hormone secretion. In conclusion, the present study improves current understanding of the molecular mechanism underlying acute gastric lesions and may assist in the treatment of gastric lesions.

View Figures

View References

1	Brodie DA and Hooke KF: The effect of vasoactive agents on stress-induced gastric hemorrhage in the rat. Digestion. 4:193–204. 1971. View Article : Google Scholar : PubMed/NCBI
2	Ernst H, Konturek PC, Brzozowski T, Lochs H, Hahn EG and Konturek SJ: Adaptation of gastric mucosa to stress. Effect of ranitidine. J Physiol Pharmacol. 49:405–419. 1998.PubMed/NCBI
3	Guo S, Gao Q, Jiao Q, Hao W, Gao X and Cao JM: Gastric mucosal damage in water immersion stress: Mechanism and prevention with GHRP-6. World J Gastroenterol. 18:3145–3155. 2012. View Article : Google Scholar : PubMed/NCBI
4	Robles TF and Carroll JE: Restorative biological processes and health. Soc Personal Psychol Compass. 5:518–537. 2011. View Article : Google Scholar : PubMed/NCBI
5	Lin HP, Lin HY, Lin WL and Huang AC: Effects of stress, depression, and their interaction on heart rate, skin conductance, finger temperature, and respiratory rate: Sympathetic-parasympathetic hypothesis of stress and depression. J Clin Psychol. 67:1080–1091. 2011. View Article : Google Scholar : PubMed/NCBI
6	Du JJ, Dou KF, Peng SY, Wang WZ, Wang ZH, Xiao HS, Guan WX, Liu YB and Gao ZQ: Down-regulated full-length novel gene GDDR and its effect on gastric cancer. Zhonghua Yi Xue Za Zhi. 83:1166–1168. 2003.(In Chinese). PubMed/NCBI
7	Du JJ, Dou KF, Peng SY, Li JT, Wang WZ, Guan WX and Gao ZQ: Study on novel gene GDDR related to gastric cancer. Zhonghua Wai Ke Za Zhi. 43:10–13. 2005.(In Chinese). PubMed/NCBI
8	May FE, Griffin SM and Westley BR: The trefoil factor interacting protein TFIZ1 binds the trefoil protein TFF1 preferentially in normal gastric mucosal cells but the co-expression of these proteins is deregulated in gastric cancer. Int J Biochem Cell Biol. 41:632–640. 2009. View Article : Google Scholar : PubMed/NCBI
9	Baus-Loncar M, Lubka M, Pusch CM, Otto WR, Poulsom R and Blin N: Cytokine regulation of the trefoil factor family binding protein GKN2 (GDDR/TFIZ1/blottin) in human gastrointestinal epithelial cells. Cell Physiol Biochem. 20:193–204. 2007. View Article : Google Scholar : PubMed/NCBI
10	Menheniott TR, O'Connor L, Chionh YT, Däbritz J, Scurr M, Rollo BN, Ng GZ, Jacobs S, Catubig A, Kurklu B, et al: Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression. J Clin Invest. 126:1383–1400. 2016. View Article : Google Scholar : PubMed/NCBI
11	Moss SF, Lee JW, Sabo E, Rubin AK, Rommel J, Westley BR, May FE, Gao J, Meitner PA, Tavares R and Resnick MB: 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. 14:4161–4167. 2008. View Article : Google Scholar : PubMed/NCBI
12	Chu G, Qi S, Yang G, Dou K, Du J and Lu Z: Gastrointestinal tract specific gene GDDR inhibits the progression of gastric cancer in a TFF1 dependent manner. Mol Cell Biochem. 359:369–374. 2012. View Article : Google Scholar : PubMed/NCBI
13	Shi LS, Wang H, Wang F, Feng M, Wang M and Guan WX: Effects of gastrokine2 expression on gastric cancer cell apoptosis by activation of extrinsic apoptotic pathways. Mol Med Rep. 10:2898–2904. 2014. View Article : Google Scholar : PubMed/NCBI
14	Kim O, Yoon JH, Choi WS, Ashktorab H, Smoot DT, Nam SW, Lee JY and Park WS: GKN2 contributes to the homeostasis of gastric mucosa by inhibiting GKN1 activity. J Cell Physiol. 229:762–771. 2014. View Article : Google Scholar : PubMed/NCBI
15	Menheniott TR, Kurklu B and Giraud AS: Gastrokines: Stomach-specific proteins with putative homeostatic and tumor suppressor roles. Am J Physiol Gastrointest Liver Physiol. 304:G109–G121. 2013. View Article : Google Scholar : PubMed/NCBI
16	Gang W, Chen F, Xiangui L, et al: The role of new gene GDDR in the acute and chronic gastric mucosal injury in mice. Progress in Modern Biomedicine. 10:1836–1839. 2015.
17	Shimozawa N, Okajima K, Harada N, Arai M, Ishida Y, Shimada S, Kurihara H and Nakagata N: Contribution of sensory neurons to sex difference in the development of stress-induced gastric mucosal injury in mice. Gastroenterology. 131:1826–1834. 2006. View Article : Google Scholar : PubMed/NCBI
18	Menheniott TR, Peterson AJ, O'Connor L, Lee KS, Kalantzis A, Kondova I, Bontrop RE, Bell KM and Giraud AS: A novel gastrokine, Gkn3, marks gastric atrophy and shows evidence of adaptive gene loss in humans. Gastroenterology. 138:1823–1835. 2010. View Article : Google Scholar : PubMed/NCBI
19	Santucci L, Fiorucci S, Giansanti M, Brunori PM, Di Matteo FM and Morelli A: Pentoxifylline prevents indomethacin induced acute gastric mucosal damage in rats: Role of tumour necrosis factor alpha. Gut. 35:909–915. 1994. View Article : Google Scholar : PubMed/NCBI
20	Trapnell C, Pachter L and Salzberg SL: TopHat: Discovering splice junctions with RNA-Seq. Bioinformatics. 25:1105–1111. 2009. View Article : Google Scholar : PubMed/NCBI
21	Gene Ontology C: The Gene Ontology (GO) project in 2006. Nucleic Acids Research. 34:D322–326. 2006. View Article : Google Scholar : PubMed/NCBI
22	Kanehisa M and Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000. View Article : Google Scholar : PubMed/NCBI
23	Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC and Lempicki RA: DAVID: Database for annotation, visualization, and integrated discovery. Genome Biol. 4:P32003. View Article : Google Scholar : PubMed/NCBI
24	Barabási AL and Oltvai ZN: Network biology: Understanding the cell's functional organization. Nat Rev Genet. 5:101–113. 2004. View Article : Google Scholar : PubMed/NCBI
25	Prieto C, Risueño A, Fontanillo C and De las Rivas J: Human gene coexpression landscape: Confident network derived from tissue transcriptomic profiles. PLoS One. 3:e39112008. View Article : Google Scholar : PubMed/NCBI
26	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
27	Wang L, Wang S and Li W: RSeQC: Quality control of RNA-seq experiments. Bioinformatics. 28:2184–2185. 2012. View Article : Google Scholar : PubMed/NCBI
28	Nishida K, Ohta Y and Ishiguro I: Changes in nitric oxide production with lesion development in the gastric mucosa of rats with water immersion restraint stress. Res Commun Mol Pathol Pharmacol. 100:201–212. 1998.PubMed/NCBI
29	S Kwiecien S, Pawlik MW, Brzozowski T, Konturek PC, Sliwowski Z, Pawlik WW and Konturek SJ: Nitric oxide (NO)-releasing aspirin and (NO) donors in protection of gastric mucosa against stress. J Physiol Pharmacol. 59 Suppl 2:S103–S115. 2008.
30	Brzozowska I, Ptak-Belowska A, Pawlik M, Pajdo R, Drozdowicz D, Konturek SJ, Pawlik WW and Brzozowski T: Mucosal strengthening activity of central and peripheral melatonin in the mechanism of gastric defense. J Physiol Pharmacol. 60 Suppl 7:47–56. 2009.PubMed/NCBI
31	Nur Azlina MF, Kamisah Y, Chua KH and Qodriyah HM: Tocotrienol attenuates stress-induced gastric lesions via activation of prostaglandin and upregulation of COX-1 mRNA. Evid Based Complement Alternat Med. 2013:8047962013. View Article : Google Scholar : PubMed/NCBI
32	Li YM, Lu GM, Zou XP, Li ZS, Peng GY and Fang DC: Dynamic functional and ultrastructural changes of gastric parietal cells induced by water immersion-restraint stress in rats. World J Gastroenterol. 12:3368–3372. 2006. View Article : Google Scholar : PubMed/NCBI
33	Brzozowski T: Role of renin-angiotensin system and metabolites of angiotensin in the mechanism of gastric mucosal protection. Curr Opin Pharmacol. 19:90–98. 2014. View Article : Google Scholar : PubMed/NCBI
34	Rohani MG and Parks WC: Matrix remodeling by MMPs during wound repair. Matrix Biol 44–46. 1–121. 2015.
35	Wilgus TA: Growth factor-extracellular matrix interactions regulate wound repair. Adv Wound Care (New Rochelle). 1:249–254. 2012. View Article : Google Scholar : PubMed/NCBI
36	Sun Z, Liu H, Yang Z, Shao D, Zhang W, Ren Y, Sun B, Lin J, Xu M and Nie S: Intestinal trefoil factor activates the PI3K/Akt signaling pathway to protect gastric mucosal epithelium from damage. Int J Oncol. 45:1123–1132. 2014. View Article : Google Scholar : PubMed/NCBI
37	Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, Lee L and Isakson P: Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. 91:pp. 12013–12017. 1994; View Article : Google Scholar : PubMed/NCBI
38	Wallace JL, McKnight W, Reuter BK and Vergnolle N: NSAID-induced gastric damage in rats: Requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology. 119:706–714. 2000. View Article : Google Scholar : PubMed/NCBI
39	Baek YH, Lee KN, Jun DW, Yoon BC, Kim JM, Oh TY and Lee OY: Augmenting effect of DA-9601 on ghrelin in an acute gastric injury model. Gut Liver. 5:52–56. 2011. View Article : Google Scholar : PubMed/NCBI
40	Adami M, Pozzoli C, Leurs R, Stark H and Coruzzi G: Histamine H(3) receptors are involved in the protective effect of ghrelin against HCl-induced gastric damage in rats. Pharmacology. 86:259–266. 2010. View Article : Google Scholar : PubMed/NCBI
41	Okajima K, Murakami K, Liu W and Uchiba M: Inhibition of neutrophil activation by ranitidine contributes to prevent stress-induced gastric mucosal injury in rats. Crit Care Med. 28:2858–2865. 2000. View Article : Google Scholar : PubMed/NCBI
42	Mifsud KR and Reul JM: Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus. Proc Natl Acad Sci USA. 113:pp. 11336–11341. 2016; View Article : Google Scholar : PubMed/NCBI
43	Filaretova LP, Filaretov AA and Makara GB: Corticosterone increase inhibits stress-induced gastric erosions in rats. Am J Physiol. 274:G1024–G1030. 1998.PubMed/NCBI
44	Lee Y, Jang AR, Francey LJ, Sehgal A and Hogenesch JB: KPNB1 mediates PER/CRY nuclear translocation and circadian clock function. ELife. 4:2015. View Article : Google Scholar
45	Zhang F, Wu W, Deng Z, Zheng X, Zhang J, Deng S, Chen J, Ma Q, Wang Y, Yu X, et al: High altitude increases the expression of hypoxia-inducible factor 1alpha and inducible nitric oxide synthase with intest-inal mucosal barrier failure in rats. Int J Clin Exp Pathol. 8:5189–5195. 2015.PubMed/NCBI
46	Bogdan C: Nitric oxide synthase in innate and adaptive immunity: An update. Trends Immunol. 36:161–178. 2015. View Article : Google Scholar : PubMed/NCBI
47	Wang T, Leng YF and Zhang Y, Xue X, Kang YQ and Zhang Y: Oxidative stress and hypoxia-induced factor 1α expression in gastric ischemia. World J Gastroenterol. 17:1915–1922. 2011. View Article : Google Scholar : PubMed/NCBI
48	Filaretova L: Glucocorticoids are gastroprotective under physiologic conditions. Ther Adv Chronic Dis. 2:333–342. 2011. View Article : Google Scholar : PubMed/NCBI
49	Filaretova LP, Podvigina TT, Bagaeva TR, Tanaka A and Takeuchi K: Mechanisms underlying the gastroprotective action of glucocorticoids released in response to ulcerogenic stress factors. Ann N Y Acad Sci. 1018:288–292. 2004. View Article : Google Scholar : PubMed/NCBI