Biological Functions and Therapeutic Potential of Lipocalin 2 in Cancer

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Jun 25

PMID 32575507

Citations 72

Authors

Ginette S Santiago-Sanchez

Valentina Pita-Grisanti

Blanca Quinones-Diaz

Kristyn Gumpper

Zobeida Cruz-Monserrate

Pablo E Vivas-Mejia

Affiliations

Soon will be listed here.

Abstract

Lipocalin-2 (LCN2) is a secreted glycoprotein linked to several physiological roles, including transporting hydrophobic ligands across cell membranes, modulating immune responses, maintaining iron homeostasis, and promoting epithelial cell differentiation. Although LNC2 is expressed at low levels in most human tissues, it is abundant in aggressive subtypes of cancer, including breast, pancreas, thyroid, ovarian, colon, and bile duct cancers. High levels of LCN2 have been associated with increased cell proliferation, angiogenesis, cell invasion, and metastasis. Moreover, LCN2 modulates the degradation, allosteric events, and enzymatic activity of matrix metalloprotease-9, a metalloprotease that promotes tumor cell invasion and metastasis. Hence, LCN2 has emerged as a potential therapeutic target against many cancer types. This review summarizes the most relevant findings regarding the expression, biological roles, and regulation of LCN2, as well as the proteins LCN2 interacts with in cancer. We also discuss the approaches to targeting LCN2 for cancer treatment that are currently under investigation, including the use of interference RNAs, antibodies, and gene editing.

Citing Articles

Distinct gene signatures define the epithelial cell features of mucinous appendiceal neoplasms and pseudomyxoma metastases.

Ayala C, Sathe A, Bai X, Grimes S, Shen J, Poultsides G Front Genet. 2025; 16:1536982.

PMID: 40018643 PMC: 11865047. DOI: 10.3389/fgene.2025.1536982.

Periprostatic Adipose Tissue as a Contributor to Prostate Cancer Pathogenesis: A Narrative Review.

Drewa J, Lazar-Juszczak K, Adamowicz J, Juszczak K Cancers (Basel). 2025; 17(3).

PMID: 39941741 PMC: 11816168. DOI: 10.3390/cancers17030372.

Explore the possible influence of Sjogren's syndrome on thyroid cancer: A literature data mining and meta-analysis.

Kong F, Han B, Wu Z, Chen J, Shen X, Shi Q PLoS One. 2025; 20(2):e0318747.

PMID: 39928612 PMC: 11809879. DOI: 10.1371/journal.pone.0318747.

Identification of Novel LCN2 Inhibitors Based on Construction of Pharmacophore Models and Screening of Marine Compound Libraries by Fragment Design.

Zheng N, Li X, Zhou N, Luo L Mar Drugs. 2025; 23(1).

PMID: 39852526 PMC: 11767183. DOI: 10.3390/md23010024.

The role of the C5a-C5aR pathway in iron metabolism and gastric cancer progression.

Ni Q, Yang H, Rao H, Zhang L, Xiong M, Han X Front Immunol. 2025; 15():1522181.

PMID: 39850877 PMC: 11754390. DOI: 10.3389/fimmu.2024.1522181.

References

Celestino R, Nome T, Pestana A, Hoff A, Goncalves A, Pereira L . CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension. BMC Cancer. 2018; 18(1):68. PMC: 5763897. DOI: 10.1186/s12885-017-3948-3. View

Chiang K, Yeh T, Wu R, Pang J, Cheng C, Wang S . Lipocalin 2 (LCN2) is a promising target for cholangiocarcinoma treatment and bile LCN2 level is a potential cholangiocarcinoma diagnostic marker. Sci Rep. 2016; 6:36138. PMC: 5080596. DOI: 10.1038/srep36138. View

Oren B, Urosevic J, Mertens C, Mora J, Guiu M, Gomis R . Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis. J Pathol. 2016; 239(3):274-85. DOI: 10.1002/path.4724. View

Furutani M, Arii S, Mizumoto M, Kato M, Imamura M . Identification of a neutrophil gelatinase-associated lipocalin mRNA in human pancreatic cancers using a modified signal sequence trap method. Cancer Lett. 1998; 122(1-2):209-14. DOI: 10.1016/s0304-3835(97)00391-1. View

Guo P, Yang J, Jia D, Moses M, Auguste D . ICAM-1-Targeted, Lcn2 siRNA-Encapsulating Liposomes are Potent Anti-angiogenic Agents for Triple Negative Breast Cancer. Theranostics. 2016; 6(1):1-13. PMC: 4679350. DOI: 10.7150/thno.12167. View

Yang J, McNeish B, Butterfield C, Moses M . Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer. FASEB J. 2012; 27(1):45-50. PMC: 3528324. DOI: 10.1096/fj.12-211730. View

Iannetti A, Pacifico F, Acquaviva R, Lavorgna A, Crescenzi E, Vascotto C . The neutrophil gelatinase-associated lipocalin (NGAL), a NF-kappaB-regulated gene, is a survival factor for thyroid neoplastic cells. Proc Natl Acad Sci U S A. 2008; 105(37):14058-63. PMC: 2544578. DOI: 10.1073/pnas.0710846105. View

Mori K, Lee H, Rapoport D, Drexler I, Foster K, Yang J . Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest. 2005; 115(3):610-21. PMC: 548316. DOI: 10.1172/JCI23056. View

Srdelic Mihalj S, Kuzmic-Prusac I, Zekic-Tomas S, Samija-Projic I, capkun V . Lipocalin-2 and matrix metalloproteinase-9 expression in high-grade endometrial cancer and their prognostic value. Histopathology. 2014; 67(2):206-15. DOI: 10.1111/his.12633. View

10.

Leung L, Radulovich N, Zhu C, Organ S, Bandarchi B, Pintilie M . Lipocalin2 promotes invasion, tumorigenicity and gemcitabine resistance in pancreatic ductal adenocarcinoma. PLoS One. 2012; 7(10):e46677. PMC: 3464270. DOI: 10.1371/journal.pone.0046677. View

11.

Chakraborty S, Kaur S, Guha S, Batra S . The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer. Biochim Biophys Acta. 2012; 1826(1):129-69. PMC: 3362670. DOI: 10.1016/j.bbcan.2012.03.008. View

12.

Kaur S, Baine M, Guha S, Ochi N, Chakraborty S, Mallya K . Neutrophil gelatinase-associated lipocalin, macrophage inhibitory cytokine 1, and carbohydrate antigen 19-9 in pancreatic juice: pathobiologic implications in diagnosing benign and malignant disease of the pancreas. Pancreas. 2012; 42(3):494-501. PMC: 3578014. DOI: 10.1097/MPA.0b013e31826a8597. View

13.

Tong Z, Kunnumakkara A, Wang H, Matsuo Y, Diagaradjane P, Harikumar K . Neutrophil gelatinase-associated lipocalin: a novel suppressor of invasion and angiogenesis in pancreatic cancer. Cancer Res. 2008; 68(15):6100-8. PMC: 2714276. DOI: 10.1158/0008-5472.CAN-08-0540. View

14.

Guo P, Huang J, Wang L, Jia D, Yang J, Dillon D . ICAM-1 as a molecular target for triple negative breast cancer. Proc Natl Acad Sci U S A. 2014; 111(41):14710-5. PMC: 4205631. DOI: 10.1073/pnas.1408556111. View

15.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

16.

Bebber C, Muller F, Prieto Clemente L, Weber J, von Karstedt S . Ferroptosis in Cancer Cell Biology. Cancers (Basel). 2020; 12(1). PMC: 7016816. DOI: 10.3390/cancers12010164. View

17.

Friedl A, Stoesz S, Buckley P, Gould M . Neutrophil gelatinase-associated lipocalin in normal and neoplastic human tissues. Cell type-specific pattern of expression. Histochem J. 1999; 31(7):433-41. DOI: 10.1023/a:1003708808934. View

18.

Bahmani P, Halabian R, Rouhbakhsh M, Roushandeh A, Masroori N, Ebrahimi M . Neutrophil gelatinase-associated lipocalin induces the expression of heme oxygenase-1 and superoxide dismutase 1, 2. Cell Stress Chaperones. 2009; 15(4):395-403. PMC: 3082646. DOI: 10.1007/s12192-009-0154-5. View

19.

Jung M, Weigert A, Mertens C, Rehwald C, Brune B . Iron Handling in Tumor-Associated Macrophages-Is There a New Role for Lipocalin-2?. Front Immunol. 2017; 8:1171. PMC: 5611490. DOI: 10.3389/fimmu.2017.01171. View

20.

Holmes M, Paulsene W, Jide X, Ratledge C, Strong R . Siderocalin (Lcn 2) also binds carboxymycobactins, potentially defending against mycobacterial infections through iron sequestration. Structure. 2005; 13(1):29-41. DOI: 10.1016/j.str.2004.10.009. View