Biological Functions and Therapeutic Potential of Lipocalin 2 in Cancer

Ginette S Santiago-Sánchez, Valentina Pita-Grisanti, Blanca Quiñones-Díaz, Kristyn Gumpper, Zobeida Cruz-Monserrate, Pablo E Vivas-Mejía, Ginette S Santiago-Sánchez, Valentina Pita-Grisanti, Blanca Quiñones-Díaz, Kristyn Gumpper, Zobeida Cruz-Monserrate, Pablo E Vivas-Mejía

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.

Keywords: LCN2-MMP-9; NGAL; cancer; lipocalin 2; oncogene; siderophore.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
LCN2 differential RNA expression in normal and tumor tissue. The Cancer Genome Atlas (TCGA) RNA-Seq datasets from healthy and tumor tissue. BRCA: breast invasive carcinoma; CESC: cervical squamous cell carcinoma and endocervical carcinoma; COAD: colon adenocarcinoma; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; ESCA: esophageal carcinoma; HNSC: head and neck squamous cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; OV: ovarian serous cystadenocarcinoma; PDAC: pancreatic ductal adenocarcinoma; PRAD: prostate adenocarcinoma; READ: rectum adenocarcinoma; STAD: stomach adenocarcinoma; THCA: thyroid carcinoma; THYM: thymic carcinoma; UCEC: uterine corpus endometrial carcinoma; UCS: uterine carcinoma.
Figure 2
Figure 2
Intracellular iron regulation by LCN2 in tumor cells. Cytokines (IL-17, IL-1β, and TNF-α) secreted by immune cells in the tumor microenvironment (TME) induce activation and binding of transcription factors (TFs) NF-κB, AP-1, PU.1, GATA-1, or C/EBPβ to the LCN2 promoter region. Transcription and secretion of LCN2 is stimulated. LCN2 in the cytoplasmic space binds to iron-loaded catecholate and re-enters tumor cells as an LCN2-catecholate-Fe3+ complex through the LCN2 receptor (LCN2R) expressed in tumor cells. Increased intracellular iron protects tumor cells from ROS-induced damage and from apoptosis, and it provides resistance to hypoxic conditions.

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