Table 2.

Selected experimental and clinical findings associated with LCN2 in hepatocellular carcinoma.

Species	Model/Sample	Experiment	Major Findings	Conclusions	Reference
Human	Serum from healthy individuals, patients with HCC or patients with cirrhosis	300 subjects were subjected to routine laboratory tests	LCN2 levels greater than 225 ng/mL have a higher diagnostic performance in HCC patients and are more accurate in differentiation between cirrhosis and HCC patients than α-fetoprotein (AFP)	LCN2 is a good candidate for HCC diagnosis and screening	[90]
Human	Tissue and serum samples from HCC patients and healthy individuals	Tissues were subjected to immunostaining and serum to Western blot analysis	Strongly elevated expression of LCN2 in diseased human liver instead of in a uniform pattern. All cells positive for either AFP or myeloperoxidase (MPO) were also strongly positive for LCN2.	LCN2 is pleiotropic, possibly participating in multiple functions in the tumor microenvironment, such as damage response, immunity, and differentiation	[53]
Human	HepG2, Huh7, SK-HEP1, and J7 HCC cell lines	HepG2 and J7 cell lines were stably transfected with stably transfected TRα1, Huh7, and J7 cell lines overexpressing LCN2	LCN2 is positively regulated by T3/TR. Overexpression of LCN2 enhanced tumor cell migration and invasion both in vitro and in vivo. LCN2-induced migration occurred by activating the Met/FAK cascade	T3/TR has a potential role of in cancer progression through regulation of LCN2 via the Met/FAK cascade	[6]
Human	THLE-2, HepG2, Hep3B, PLC/PRF/5 (Alexander cells), SH-JI, and SK-HEP-1 cell lines	Adenoviral transduction of Lcn2 and knockdown of Lcn2 by short hairpin RNA (shRNA)	Adenoviral upregulation of LCN2 causes the downregulation of epithelial-to-mesenchymal markers, while silencing reverses that effect	LCN2 negatively modulates the EMT in HCC through the epidermal growth factor (TGF-β1)/Lcn2/Twist1 pathway	[7]
Human	Huh-7 and SK-Hep-1 cell lines	Cells were transfected with plasmids encoding full-length LCN2	LCN2 overexpression dramatically inhibited cell viability, induced apoptosis features reflected in cell-cycle arrest in sub-G1 phase, DNA fragmentation, and condensation of chromatin	LCN2 induces apoptosis in human hepatocellular carcinoma cells by activating mitochondrial pathways.	[4]
Human	Urine of HCC patients, patients with chronic viral hepatitis and cirrhotic patients	Urinary LCN2 levels were measured by an enzyme-linked immunosorbent assay	Urinary LCN2 content can discriminate between HCC and cirrhosis	Urinary LCN2 is a possible diagnostic marker for HCC patients	[91]
Human	102 primary HCC tissues, 74 nontumor liver tissues, seven benign liver tumor samples, 10 metastatic cancers, and 10 HCC cell lines	DNA microarray analysis done on tissues and cell lines	LCN2 is one of the top 10 genes overexpressed in HCC	This research is a step to define new candidate oncogenes and therapeutic targets in HCC	[92]
Human	25 hepatocellular carcinoma patients, hepatitis C patients, and 25 healthy subjects as a control	Measurements for hepatitis B surface antigen, hepatitis C antibodies, AFP, MMP-9, TIMP-1, and LCN2	Increased levels of LCN2 in HCC and HBV patients	LCN2 can be used as a future diagnostic marker with better sensitivity and specificity than MMP-9 for the progression of HCC	[93]
Human	Tumor tissues from 138 patients who underwent curative resection of HCC	Immunohistochemistry on tumor tissues	LCN2 and NGALR are both upregulated in HCC tissues and are associated with vascular invasion, tumor, nodes and metastasis (TNM) stage, tumor recurrence, and overall survival	LCN2 and NGALR expression might be served as novel prognostic factors and potential therapeutic targets in HCC	[94]
Human	HCC tissues and corresponding non-neoplastic liver tissues. Chang liver and SK-Hep1 human HCC cells	Tissue microarray experiment and analysis of Lcn2 expressing HCC cells	Significant increase in LCN2 levels in human HCC tissues compared with non-tumor liver tissues. Ectopic expression of LCN2 in HCC cells significantly inhibited the growth of HCC cells in vitro and in vivo, reduced the invasive potential of cells, and inhibited the expression of MMP-2 partly through JNK PI3K/AKT signalling.	LCN2 inhibits the proliferation and invasion of HCC cells through a blockade of JNK and PI3K/AKT signalling	[95]
Human	55 cases of biopsied tissues for HCC, liver cancer cells	Pharmacogenomic data analysis to discover drug–mutation interactions in cancer cells	Liver cancer patients non-responding to sorafenib treatment exhibit higher expression of extracellular sulfatase (SULF2) and LCN2. SULF2 mutation or inhibition enhances sorafenib sensitivity in liver cancer cells.	Diagnostic or therapeutic targeting of SULF2 and/or LCN2 can be a novel precision strategy for sorafenib treatment in HCC	[96]
Mouse	Tissue and serum samples from mouse model of HCC	Western blot analysis and immunostaining	LCN2 overexpression in HCC livers in mouse liver, both in transcriptional and protein levels specifically in the tumoral area extracts	LCN2 is a pleiotropic protein, possibly participating in multiple functions in the tumor microenvironment, such as damage response, immunity, and differentiation	[53]
Mouse	Implantation of tumors in nude mice	Mice were injected with Lcn2 overexpressing cell lines (i.e., SK-Hep1 cells)	Lcn2 expressing cells formed far fewer metastatic nodules in the lungs	Lcn2 inhibits proliferation, invasion, and metastasis in vitro and in vivo through transcriptional suppression of Twist1 in HCC cells	[7]