Over expressions of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in human uterine cervical neoplasms enhance tumor invasion

Objective: Accumulating evidence has demonstrated upregulation of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) in multiple malignancies which play a critical role in tumor progression. However, up to now little is known about the role played by NGAL in human uterine cervical carcinomas. In this retrospective study we aimed to evaluate the role of tissue expressions of NGAL and KIM-1 in a spectrum of uterine invasive and noninvasive cervical neoplasms. Methods: Immunohistochemical NGAL and KIM-1 expressions were investigated in a total of 107 formalin-fixed, paraffin-embedded uterine cervical tumor specimens and their association with different clinicopathologic parameters was evaluated. Results: In this series, cases with 30 low- and 29 high- grade cervical squamous intraepithelial lesion (SIL), 27 squamous cell carcinoma (SCC), 15 adenosquamous carcinoma (ASC) and 6 adenocarcinoma (ACs) were detected. Positive NGAL expression was detected in only inflammatory cells of cases, whereas KIM-1 expression was detected in tumor cells. Statistically it was determined that the positivity rate of strong NGAL and KIM-1 expression was prominently higher in invasive carcinomas when compared with non-invasive squamous cell neoplasms (P < 0.01). KIM-1 expressions were not detected in any of the few cases with adenocarcinoma. Conclusion: Our findings have showed the presence of a correlation between membranous and cytoplasmic expressions of NGAL and KIM-1 and the invasive characteristics of uterine cervical neoplasms. As a result, expressions of NGAL and KIM-1 may be important in foreseeing the invasion and tumor progression.

Adenosquamous carcinoma; Adenocarcinoma; Low- grade squamous intraep-ithelial lesions; High- grade squamous intraepithelial lesions; NGAL; KIM-1; Squamous cell carcinoma; Uterine cervix

[1] Devarajan P. Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of kidney disease. Scandinavian Journal of Clinical and Laboratory Investigation. 2008; 241: 89-94.

[2] Ding H, He Y, Li K, Yang J, Li X, Lu R, et al. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy. Clinical Immunology. 2007; 123: 227-234.

[3] Mori K, Nakao K. Neutrophil gelatinase-associated lipocalin as the real-time indicator of active kidney damage. Kidney International. 2007; 71: 967-970.

[4] Bolignano D, Donato V, Coppolino G, Campo S, Buemi A, Lacquaniti A, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. American Journal of Kidney Diseases. 2008; 52: 595-605.

[5] Kjeldsen L, Johnsen AH, Sengeløv H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. Journal of Biological Chemistry. 1993; 268: 10425-10432.

[6] Bratt T. Lipocalins and cancer. Biochimica et Biophysica Acta. 2000; 1482: 318-326.

[7] Bolignano D, Donato V, Lacquaniti A, Fazio MR, Bono C, Coppolino G, et al. Neutrophil gelatinase-associated lipocalin (NGAL) in human neoplasias: a new protein enters the scene. Cancer Letters. 2010; 288: 10-16.

[8] Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. Journal of Biological Chemistry. 1998; 273: 4135-4142.

[9] Zhang PL, Mashni JW, Sabbisetti VS, Schworer CM, Wilson GD, Wolforth SC, et al. Urine kidney injury molecule-1: a potential non-invasive biomarker for patients with renal cell carcinoma. International Urology and Nephrology. 2014; 46: 379-388.

[10] Sinha V, Vence LM, Salahudeen AK. Urinary tubular protein-based biomarkers in the rodent model of cisplatin nephrotoxicity. Journal of Investigative Medicine. 2013; 61: 564-568.

[11] Kurman RJ, Ellenson LH, Ronnett BM. Bleustein’s Pathology of the Female Genital Tract (pp. 286-287). Sixth Ed. New York: Springer. 2011.

[12] Contag SA, Gostout BS, Clayton AC, Dixon MH, McGovern RM, Calhoun ES. Comparison of gene expression in squamous cell carcinoma and adenocarcinoma of the uterine cervix. Gynecologic Oncology. 2004; 95: 610-617.

[13] Lei J, Andrae B, Ploner A, Lagheden C, Eklund C, Nordqvist Kleppe S, et al. Cervical screening and risk of adenosquamous and rare histological types of invasive cervical carcinoma: population based nested case-control study. British Medical Journal. 2019; 365: 1207

[14] Diniz G, Karadeniz T, Sayhan S, Akata T, Aydiner F, Ayaz D, et al. Tissue expression of human epididymal secretory protein 4 may be useful in the differential diagnosis of uterine cervical tumors. Ginekologia Polska. 2017; 88: 51-55.

[15] Solakoglu Kahraman D, Diniz G, Sayhan S, Ayaz D, Uncel M, Karadeniz T, et al. Differences in the ARID-1 alpha expressions in squamous and adenosquamous carcinomas of uterine cervix. AP-MIS. 2015; 123: 847-850.

[16] Candido S, Maestro R, Polesel J, Catania A, Maira F, Signorelli SS, et al. Roles of neutrophil gelatinase-associated lipocalin (NGAL) in human cancer. Oncotarget. 2014; 5: 1576-1594.

[17] Liu F, Li N, Yang W, Wang R, Yu J, Wang X. The expression analysis of NGAL and NGALR in clear cell renal cell carcinoma. Gene. 2018; 676: 269-278.

[18] Ruiz-Morales JM, Dorantes-Heredia R, Arrieta O, Chávez-Tapia NC, Motola-Kuba D. Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) prognostic value in lung adenocarcinoma. Tumor Biology. 2015; 36: 3601-3610.

[19] Miharada K, Hiroyama T, Sudo K, Danjo I, Nagasawa T, Nakamura Y. Lipocalin 2-mediated growth suppression is evident in human erythroid and monocytemacrophage lineage cells. Journal of Cellular Physiology. 2008; 215: 526-537.

[20] Janowska-Wieczorek A, Marquez L, Matsuzaki A, Hashmi H, Larratt L, Boshkov L, et al. Expression of matrix metallopro-teinases (MMP-2 and -9) and tissue inhibitors of metallopro-teinases (TIMP-1 and -2) in acute myelogenous leukaemia blasts: comparison with normal bone marrow cells. British Journal of Haematology. 1999; 105: 402-411.

[21] Solakoglu Kahraman D, Diniz G, Kaya Ö, Ceylan C. KIM1 and NGAL expression in patients with multiple myeloma and clini-copathological significance. İstanbul Kanuni Sultan Süleyman Tıp Dergisi. 2019.

[22] Monisha J, Roy N, Padmavathi G, Banik K, Bordoloi D, Khwairak-pam A, et al. NGAL is Downregulated in oral squamous cell carcinoma and leads to increased survival, proliferation, migration and chemoresistance. Cancers. 2018; 10: 228.

[23] Javadi M, Ganesan P, Bordoloi D, Roy Nk, Kunnumakkara A. Neutrophil gelatinase-associated lipocalin (NGAL): a promising biomarker for cancer diagnosis and a potential target for cancer therapeutics. Journal of Cell Science and Molecular Biology. 2014; 1: 106.

[24] Tang J, Li J, Li S, Li J, Yu C, Wei C. Effect of inhibiting NGAL gene expression on a549 lung cancer cell migration and invasion. Chinese Journal of Lung Cancer. 2015; 18: 187-192.

[25] Wang P, Ko J, Yang S, Lin L. Implication of human nonmetastatic clone 23 Type 1 and its downstream gene lipocalin 2 in metastasis and patient’s survival of cancer of uterine cervix. International Journal of Cancer. 2011; 129: 2380-2389.

[26] Song B, Zhang H, Jiang L, Chi Y, Tian J, Du W, et al. Down-regulation of lipocalin 2 suppresses the growth of human lung ade-nocarcinoma through oxidative stress involving Nrf2/HO-1 sig-naling. Acta Biochimica et Biophysica Sinica. 2015; 47: 805-814.

[27] Wang P, Yang S, Tseng C, Ying T, Ko J, Lin L. The role of lipocalin 2 and its concernment with human nonmetastatic clone 23 type 1 and p53 in carcinogenesis of uterine cervix. Reproductive Sciences. 2011; 18: 447-455.

[28] Syrjänen S, Naud P, Sarian L, Derchain S, Roteli-Martins C, Tatti S, et al. Up-regulation of lipocalin 2 is associated with high-risk human papillomavirus and grade of cervical lesion at baseline but does not predict outcomes of infections or incident cervical in-traepithelial neoplasia. American Journal of Clinical Pathology. 2010; 134: 50-59.

[29] Ersavaş S, Diniz G, Yildirim HT, Koca Y, Kahraman DS, Ayaz D, et al. Expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in wilms tumor. Turkish Journal of Pathology. 2016; 32: 158-163.