Overexpression of neutrophil gelatinase-associated lipocalin and its receptor in colorectal carcinoma: Significant correlation with cell differentiation and tumour invasion

Lv,Zhuo; Xu,Li-Yan; Shen,Zhong-Ying; Zhang,Fa-Ren; Xu,Xiu-E; Li,En-Min

doi:10.3892/ol_00000019

Overexpression of neutrophil gelatinase-associated lipocalin and its receptor in colorectal carcinoma: Significant correlation with cell differentiation and tumour invasion

Authors:
- Zhuo Lv
- Li-Yan Xu
- Zhong-Ying Shen
- Fa-Ren Zhang
- Xiu-E Xu
- En-Min Li
View Affiliations

Affiliations: Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou 515041, P.R. China
Published online on: January 1, 2010 https://doi.org/10.3892/ol_00000019
Pages: 103-108

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

Neutrophil gelatinase-associated lipocalin (NGAL), a member of the lipocalin family, is related to imflammation and tumour. Recently, a specific cell-surface receptor (24p3R/NGALR) for lipocalin 24p3 was reported. However, the characteristics of NGALR expression in colorectal carcinoma (CRC) are not known. The objectives of this study were to investigate the expression of NGAL and NGALR in CRC specimens, and determine any relationship between the expression of these proteins and tumour progression. In the present study, CRC specimens of 102 patients were obtained, and the expression of NGAL, NGALR, ferritin and Ki67 was analyzed in paraffin sections by immunohistochemistry. Statistical analyses of the data collected were performed with SPSS software. We found that the cytoplasmic staining of NGAL, NGALR and ferritin, as well as the nuclear staining of Ki67 were significantly up-regulated in CRC tissues compared with normal colorectal tissues. Expression of NGAL was related to the deeper invasion of CRC (P=0.026), while NGALR was significantly associated with a deeper invasion (P=0.018) and a high degree of Tumor, Node and Metastasis stages (P=0.042) in CRC. The NGAL/NGALR co-expression was associated with poor cellular differentiation (P=0.004). Positive correlations between NGAL and NGALR (r=0.432, P<0.01), NGAL and ferritin (r=0.374, P<0.001), NGALR and Ki67 (r=0.228, P<0.05), NGAL/NGALR co-expression and ferritin (r=0.349, P<0.001), as well as NGAL/NGALR co-expression and Ki67 (r=0.205, P<0.05) were observed. However, the expression of NGAL or NGALR was not significantly associated with patient survival. These findings detected an elevated expression of NGAL and NGALR resulting in poor cellular differentiation and a deeper invasion of CRC. Thus, NGALR may be a novel target for the treatment of CRC.

View Figures

View References

1	Sung JJ, Lau JY, Goh KL and Leung WK: Increasing incidence of CRC in Asia: implications for screening. Lancet Oncol. 6:871–876. 2005. View Article : Google Scholar
2	Kjeldsen L, Johnsen AH, Sengeløv H and Borregaard N: Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem. 268:10425–10432. 1993.PubMed/NCBI
3	Zhang H, Xu L, Xiao D, Xie J, Zeng H, Wang Z, Zhang X, Niu Y, Shen Z, Shen J, Wu X and Li E: Upregulation of neutrophil gelatinase-associated lipocalin in oesophageal squamous cell carcinoma: significant correlation with cell differentiation and tumour invasion. J Clin Pathol. 60:555–561. 2007. View Article : Google Scholar
4	Stoesz SP, Friedl A, Haag JD, Lindstrom MJ, Clark GM and Gould MN: Heterogeneous expression of the lipocalin NGAL in primary breast cancers. Int J Cancer. 79:565–572. 1998. View Article : Google Scholar : PubMed/NCBI
5	Furutani M, Arii S, Mizumoto M, Kato M and Imamura M: Identification of a neutrophil gelatinase-associated lipocalin mRNA in human pancreatic cancers using a modified signal sequence trap method. Cancer Lett. 122:209–214. 1998. View Article : Google Scholar
6	Bartsch S and Tschesche H: Cloning and expression of human neutrophil lipocalin cDNA derived from bone marrow and ovarian cancer cells. FEBS Lett. 357:255–259. 1995. View Article : Google Scholar : PubMed/NCBI
7	Woo HJ, Park JC, Bae CH, Song SY, Lee HM and Kim YD: Up-regulation of neutrophil gelatinase-associated lipocalin in cholesteatoma. Acta Otolaryngol. 21:1–6. 2008.
8	Xu LY, Li EM, Xiong HQ, Shen ZY and Cai WJ: Study of neutrophil gelatinase-associated lipocalin (NGAL) gene overexpression in the progress of malignant transformation of human immortalized esophageal epithelial cell. Prog Biochem Biophys. 28:839–843. 2001.
9	Li EM, Xu LY, Cai WJ, Xiong HQ, Shen ZY and Zeng Y: Functions of neutrophil gelatinase-associated lipocalin in the esophageal carcinoma cell line SHEEC. Acta Biochim Biophys Sin. 35:247–254. 2003.PubMed/NCBI
10	Lin JL, Xu LY, Li EM, Cai WJ, Niu YD, Fang KY, Xiong HQ, Shen ZY and Zeng Y: Antisense blocking of NGAL gene expression affects the microfilament cytoskeleton in SHEEC esophageal cancer cells. Prog Biochem Biophys. 31:409–415. 2004.
11	Nielsen BS, Borregaard N, Bundgaard JR, Timshel S, Sehested M and Kjeldsen L: Induction of NGAL synthesis in epithelial cells of human colorectal neoplasia and inflammatory bowel diseases. Gut. 38:414–420. 1996. View Article : Google Scholar : PubMed/NCBI
12	Lee HJ, Lee EK, Lee KJ, Hong SW, Yoon Y and Kim JS: Ectopic expression of neutrophil gelatinase-associated lipocalin suppresses the invasion and liver metastasis of colon cancer cells. Int J Cancer. 118:2490–2497. 2006. View Article : Google Scholar
13	Flower DR: Beyond the superfamily: the lipocalin receptors. Biochim Biophys Acta. 1482:327–336. 2000. View Article : Google Scholar : PubMed/NCBI
14	Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN and Strong RK: The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell. 10:1033–1043. 2002. View Article : Google Scholar : PubMed/NCBI
15	Yang J, Mori K, Li JY and Barasch J: Iron, lipocalin, and kidney epithelia. Am J Physiol Renal Physiol. 285:F9–F18. 2003. View Article : Google Scholar : PubMed/NCBI
16	Yang J, Goetz D, Li J-Y, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R and Barasch J: An iron delivery pathway mediated by a lipocalin. Mol Cell. 10:1045–1056. 2002. View Article : Google Scholar : PubMed/NCBI
17	Devireddy LR, Gazin C, Zhu X and Green MR: A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell. 123:1293–1305. 2005. View Article : Google Scholar : PubMed/NCBI
18	Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, Schmidt-Ott KM, Chen X, Li JY, Weiss S, Mishra J, Cheema FH, Markowitz G, Suganami T, Sawai K, Mukoyama M, Kunis C, D’Agati V, Devarajan P and Barasch J: Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest. 115:610–621. 2005. View Article : Google Scholar : PubMed/NCBI
19	Wurzelmann JI, Silver A, Schreinemachers DM, Sandler RS and Everson RB: Iron intake and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 5:503–507. 1996.PubMed/NCBI
20	Stone WL, Krishnan K, Campbell SE, Qui M, Whaley SG and Yang H: Tocopherols and the treatment of colon cancer. Ann N Y Acad Sci. 1031:223–233. 2004. View Article : Google Scholar : PubMed/NCBI
21	Sawa T, Akaike T, Kida K, Fukushima Y, Takagi K and Maeda H: Lipid peroxyl radicals from oxidized oils and heme-iron: implication of a high-fat diet in colon carcinogenesis. Cancer Epidemiol Biomarkers Prev. 7:1007–1012. 1998.PubMed/NCBI
22	Lund EK, Fairweather-Tait SJ, Wharf SG and Johnson IT: Chronic exposure to high levels of dietary iron fortification increases lipid peroxidation in the mucosa of the rat large intestine. J Nutr. 131:2928–2931. 2001.PubMed/NCBI
23	Kuratko CN: Decrease of manganese superoxide dismutase activity in rats fed high levels of iron during colon carcinogenesis. Food Chem Toxicol. 36:819–824. 1998. View Article : Google Scholar : PubMed/NCBI
24	Valko M, Rhodes CJ, Moncol J, Izakovic M and Mazur M: Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 160:1–40. 2006. View Article : Google Scholar : PubMed/NCBI
25	Yan L, Borregaard N, Kjeldsen L and Moses MA: The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). J Biol Chem. 276:37258–37265. 2001. View Article : Google Scholar : PubMed/NCBI
26	Tschesche H, Zölzer V, Triebel S and Bartsch S: The human neutrophil lipocalin supports the allosteric activation of matrix metalloproteinases. Eur J Biochem. 268:1918–1928. 2001. View Article : Google Scholar : PubMed/NCBI
27	Fernández CA, Yan L, Louis G, Yang J, Kutok JL and Moses MA: The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin Cancer Res. 11:5390–5395. 2005.
28	Klonisch T, Bialek J, Radestock Y, Hoang-Vu C and Hombach-Klonisch S: Relaxin-like ligand-receptor systems are autocrine/paracrine effectors in tumor cells and modulate cancer progression and tissue invasiveness. Adv Exp Med Biol. 612:104–118. 2007. View Article : Google Scholar
29	Armstrong AP, Miller RE, Jones JC, Zhang J, Keller ET and Dougall WC: RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate. 68:92–104. 2008. View Article : Google Scholar : PubMed/NCBI
30	Koshiba T, Hosotani R, Miyamoto Y, Ida J, Tsuji S, Nakajima S, Kawaguchi M, Kobayashi H, Doi R, Hori T, Fujii N and Imamura M: Expression of stromal cell-derived factor 1 and CXCR4 ligand receptor system in pancreatic cancer: a possible role for tumor progression. Clin Cancer Res. 6:3530–3535. 2000.PubMed/NCBI