Association between CXCR2 and IL-22BP expression indicate a poor outcome for gastric adenocarcinoma progression

Yang,Shi  Bin; Han,Fanghai; Wu,Jian  Hai; Zhao,Zhi; Zhan,Wenhua

doi:10.3892/ol.2016.4790

Association between CXCR2 and IL-22BP expression indicate a poor outcome for gastric adenocarcinoma progression

Authors:
- Shi Bin Yang
- Fanghai Han
- Jian Hai Wu
- Zhi Zhao
- Wenhua Zhan
View Affiliations

Affiliations: Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat‑Sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: June 28, 2016 https://doi.org/10.3892/ol.2016.4790
Pages: 1477-1484

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

C-X-C motif chemokine receptor type 2 (CXCR2), a key regulatory protein, has been associated with multiple roles in the progression of numerous tumors, including gastric adenocarcinoma (GA). However, the mechanism of CXCR2 in the development of tumors remains controversial and unclear. In a previous study, the expression of CXCR2 and interleukin‑22 receptor 2 (IL‑22BP) was observed in GA. This promoted the present study, which aimed to explore the association between the two proteins, and to further analyze their roles in GA. CXCR2 and IL‑22BP protein expression was analyzed by immunohistochemistry and reverse transcription‑quantitative polymerase chain reaction assays in gastric cancer (GC) tissue, additionally confirmed via western blotting and immunocytochemical analysis in the MKN-45, BGC-823 and SGC-7901 cell lines. The association between expression levels and clinicopathological characteristics was evaluated by the Mann‑Whitney U and Kruskal-Wallis tests. Using Kaplan‑Meier plots and Cox proportional hazard models, overall survival (OS) was analyzed. Compared with non‑cancerous tissue, CXCR2 and IL‑22BP were over expressed (P<0.001 and P<0.001, respectively), and were observed mainly in the cytoplasm (P=0.022 and P=0.014, respectively) in GA. The associated protein and messenger RNA levels were analyzed, and coexpression was identified. Increased expression and more positive cases of CXCR2 and IL‑22BP were observed with advanced pathological tumor‑node‑metastasis (p‑TNM) stage in GC (P<0.001 and P<0.001, respectively), as well as the presence and absence of lymph node metastasis (LNM) (P=0.003 and P=0.041, respectively) and deep or superficial muscular invasion (P=0.002 and P=0.004, respectively). In addition, an association between IL‑22BP and tumor diameter was indicated (P=0.021). In a Kaplan‑Meier analysis, compared with negative expression, the two proteins identified a group of patients with the shortest OS. Cox proportional hazard models revealed that the two proteins, in addition to p‑TNM stage, LNM and depth of invasion, predicted a short time to OS. The coexpression of CXCR2 and IL‑22BP was demonstrated in GA, which may indicate that CXCR2 is involved in more complex mechanisms and roles, and indicate a poor outcome in GA progression.

View Figures

View References

1	Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar : PubMed/NCBI
2	Wang CS, Hsieh CC, Chao TC, Jan YY, Jeng LB, Hwang TL, Chen MF, Chen PC, Chen JS and Hsueh S: Resectable gastric cancer: Operative mortality and survival analysis. Chang Gung Med J. 25:216–227. 2002.PubMed/NCBI
3	Bernal C, Aguayo F, Villarroel C, Vargas M, Díaz I, Ossandon FJ, Santibáñez E, Palma M, Aravena E, Barrientos C and Corvalan AH: Reprimo as a potential biomarker for early detection in gastric cancer. Clin Cancer Res. 14:6264–6269. 2008. View Article : Google Scholar : PubMed/NCBI
4	Marrelli D, Roviello F, De Stefano A, Farnetani M, Garosi L, Messano A and Pinto E: Prognostic significance of CEA, CA 19-9 and CA 72-4 preoperative serum levels in gastric carcinoma. Oncology. 57:55–62. 1999. View Article : Google Scholar : PubMed/NCBI
5	DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N and Coussens LM: CD4 (+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 16:91–102. 2009. View Article : Google Scholar : PubMed/NCBI
6	Ikushima H and Miyazono K: TGFbeta signalling: A complex web in cancer progression. Nat Rev Cancer. 10:415–424. 2010. View Article : Google Scholar : PubMed/NCBI
7	Balkwill F, Charles KA and Mantovani A: Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell. 7:211–217. 2005. View Article : Google Scholar : PubMed/NCBI
8	Cheng WL, Wang CS, Huang YH, Tsai MM, Liang Y and Lin KH: Overexpression of CXCL1 and its receptor CXCR2 promote tumor invasion in gastric cancer. Ann Oncol. 22:2267–2276. 2010. View Article : Google Scholar
9	Wang CS, Lin KH, Chen SL, Chan YF and Hsueh S: Overexpression of SPARC gene in human gastric carcinoma and its clinic-pathologic significance. Br J Cancer. 91:1924–1930. 2004. View Article : Google Scholar : PubMed/NCBI
10	Wang D, Yang W, Du J, Devalaraja MN, Liang P, Matsumoto K, Tsubakimoto K, Endo T and Richmond A: MGSA/GRO-mediated melanocyte transformation involves induction of Ras expression. Oncogene. 19:4647–4659. 2000. View Article : Google Scholar : PubMed/NCBI
11	Murphy PM: The molecular biology of leukocyte chemoattractant receptors. Annu Rev Immunol. 12:593–633. 1994. View Article : Google Scholar : PubMed/NCBI
12	Kelvin DJ, Michiel DF, Johnston JA, Lloyd AR, Sprenger H, Oppenheim JJ and Wang JM: Chemokines and serpentines: The molecular biology of chemokine receptors. J Leukoc Biol. 54:604–612. 1993.PubMed/NCBI
13	Ahuja SK and Murphy PM: The CXC chemokines growth-regulated oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2 and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor. J Biol Chem. 271:20545–20550. 1996. View Article : Google Scholar : PubMed/NCBI
14	Ahuja SK, Lee JC and Murphy PM: CXC chemokines bind to unique sets of selectivity determinants that can function independently and are broadly distributed on multiple domains of human interleukin-8 receptor B. Determinants of high affinity binding and receptor activation are distinct. J Biol Chem. 271:225–232. 1996. View Article : Google Scholar : PubMed/NCBI
15	Fan X, Patera AC, Pong-Kennedy A, Deno G, Gonsiorek W, Manfra DJ, Vassileva G, Zeng M, Jackson C, Sullivan L, et al: Murine CXCR1 is a functional receptor for GCP-2/CXCL6 and interleukin-8/CXCL8. J Biol Chem. 282:11658–11666. 2007. View Article : Google Scholar : PubMed/NCBI
16	Tazawa H, Okada F, Kobayashi T, Tada M, Mori Y, Une Y, Sendo F, Kobayashi M and Hosokawa M: Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells: Implication of inflammation-associated carcinogenesis and tumor progression. Am J Pathol. 163:2221–2232. 2003. View Article : Google Scholar : PubMed/NCBI
17	Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, Diepolder H, Marquardt A, Jagla W, Popp A, et al: IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol. 290:G827–G838. 2006. View Article : Google Scholar : PubMed/NCBI
18	Wolk K, Witte E, Hoffmann U, Doecke WD, Endesfelder S, Asadullah K, Sterry W, Volk HD, Wittig BM and Sabat R: IL-22 induces lipopolysaccharide-binding protein in hepatocytes: A potential systemic role of IL-22 in Crohn's disease. J Immunol. 178:5973–5981. 2007. View Article : Google Scholar : PubMed/NCBI
19	Xu W, Presnell SR, Parrish-Novak J, Kindsvogel W, Jaspers S, Chen Z, Dillon SR, Gao Z, Gilbert T, Madden K, et al: A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc Natl Acad Sci USA. 98:9511–9516. 2001. View Article : Google Scholar : PubMed/NCBI
20	Witte E, Witte K, Warszawska K, Sabat R and Wolk K: Interleukin-22: A cytokine produced by T, NK and NKT cell subsets, with importance in the innate immune defense and tissue protection. Cytokine Growth Factor Rev. 21:365–379. 2010. View Article : Google Scholar : PubMed/NCBI
21	Sonnenberg GF, Fouser LA and Artis D: Border patrol: Regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol. 12:383–390. 2011. View Article : Google Scholar : PubMed/NCBI
22	Huber S, Gagliani N, Zenewicz LA, Huber FJ, Bosurgi L, Hu B, Hedl M, Zhang W, O'Connor W Jr, Murphy AJ, et al: IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature. 491:259–263. 2012. View Article : Google Scholar : PubMed/NCBI
23	Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S and Flavell RA: Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 29:947–957. 2008. View Article : Google Scholar : PubMed/NCBI
24	Zurleni T, Gjoni E, Ballabio A, Casieri R, Ceriani P, Marzoli L and Zurleni F: Sixth and seventh tumor-node-metastasis staging system compared in gastric cancer patients. World J Gastrointest Surg. 5:287–293. 2013. View Article : Google Scholar : PubMed/NCBI
25	Hsu SM, Raine L and Fanger H: The use of antiavidin antibody and avidin-biotin-peroxidase complex in immunoperoxidase technics. Am J Clin Pathol. 75:816–821. 1981. View Article : Google Scholar : PubMed/NCBI
26	Hsu SM, Raine L and Fanger H: Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 29:577–580. 1981. View Article : Google Scholar : PubMed/NCBI
27	Harvey JM, Clark GM, Osborne CK and Allred DC: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 17:1474–1481. 1999.PubMed/NCBI
28	Lazennec G and Richmond A: Chemokines and chemokine receptors: New insights into cancer-related inflammation. Trends Mol Med. 16:133–144. 2010. View Article : Google Scholar : PubMed/NCBI
29	Washington K: 7th edition of the AJCC cancer staging manual: Stomach. Ann Surg Oncol. 17:3077–3079. 2010. View Article : Google Scholar : PubMed/NCBI
30	Heidemann J, Ogawa H, Dwinell MB, Rafiee P, Maaser C, Gockel HR, Otterson MF, Ota DM, Lugering N, Domschke W and Binion DG: Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2. J Biol Chem. 278:8508–8515. 2003. View Article : Google Scholar : PubMed/NCBI
31	Mestas J, Burdick MD, Reckamp K, Pantuck A, Figlin RA and Strieter RM: The role of CXCR2/CXCR2 ligand biological axis in renal cell carcinoma. J Immunol. 175:5351–5357. 2005. View Article : Google Scholar : PubMed/NCBI
32	Yang G, Rosen DG, Zhang Z, Bast RC Jr, Mills GB, Colacino JA, Mercado-Uribe I and Liu J: The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc Natl Acad Sci USA. 103:16472–16477. 2006. View Article : Google Scholar : PubMed/NCBI
33	Tekamp-Olson P, Gallegos C, Bauer D, McClain J, Sherry B, Fabre M, van Deventer S and Cerami A: Cloning and characterization of cDNAs for murine macrophage inflammatory protein 2 and its human homologues. J Exp Med. 172:911–919. 1990. View Article : Google Scholar : PubMed/NCBI
34	Bozic CR, Kolakowski LF Jr, Gerard NP, Garcia-Rodriguez C, von Uexkull-Guldenband C, Conklyn MJ, Breslow R, Showell HJ and Gerard C: Expression and biologic characterization of the murine chemokine KC. J Immunol. 154:6048–6057. 1995.PubMed/NCBI
35	Harada A, Kuno K, Nomura H, Mukaida N, Murakami S and Matsushima K: Cloning of a cDNA encoding a mouse homolog of the interleukin-8 receptor. Gene. 142:297–300. 1994. View Article : Google Scholar : PubMed/NCBI
36	Martin JC, Bériou G, Heslan M, Chauvin C, Utriainen L, Aumeunier A, Scott CL, Mowat A, Cerovic V, Houston SA, et al: Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal Immunol. 7:101–113. 2014. View Article : Google Scholar : PubMed/NCBI
37	Dumoutier L, Lejeune D, Colau D and Renauld JC: Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22. J Immunol. 166:7090–7095. 2001. View Article : Google Scholar : PubMed/NCBI