Hierarchical and selective roles of galectins in hepatocarcinogenesis, liver fibrosis and inflammation of hepatocellular carcinoma

Table 1 Involvement of galectins in the pathogenesis of hepatocellular carcinoma

Galectin member	Expression	Function and/or effect	Model	Ref.
Galectin-1	Up-regulated (mRNA and protein) in HCC, secreted by tumor hepatocytes and accumulated in stroma surrounding HCC	Correlates with tumor aggressiveness, metastases and enhanced risk of post-operative recurrence	Human HCC tissues	[79-82]
		Favors HCC cell adhesion to ECM, cell migration and invasion	Human HCC cell lines	[81,85]
		Increases tumor growth and metastasis in draining-tumor lymph nodes	Nude mice injected with galectin-1 over-expressing HepG2 cells	[85]
		Possible role in the suppression of antitumor immune responses	Human HCC tissues	[82]
Galectin-3	Up-regulated (mRNA and protein) in HCC. Transactivation of murine LGALS3 promoter can occur by HBV-X protein.		Human HCC tissues and cell lines	[79,124,125]
	High nuclear expression	Correlates with histological differentiation and vascular invasion	Human HCC tissues	[126]
	Up-regulated in HCC-associated capillary endothelial cells	Probably promotes angiogenesis	Tumor-associated endothelial cells isolated from rats	[128]
Galectin-4	Higher expression in HCC than normal tissues		Human HCC tissues and cell lines	[154]
Galectin-8	Diminished expression in hepatoblastoma and hepatocarcinoma		Human HCC tissues	[159]
Galectin-9	Downregulated in HCC	Galectin-9 suppression promotes cell proliferation and adhesion to ECM, tumor cell-endothelial cell adhesion and trans-endothelial invasion of HepG2 cells.	Human cell lines	[181]
		Downregulation of galectin-9 represents a risk factor for patient survival, correlates with tumor histopathological grade, vascular invasion and metastasis	Human HCC tissues	[181]

HCC: Hepatocellular carcinoma; ECM: Extracellular matrix; HBV: Hepatitis B virus.

Table 2 Galectins in inflammation-associated liver injury

Galectin member	Experimental model		Role	Effects	Ref.
Galectin-1	Hepatitis induced by injection of Con A		Protective	Prevents both liver injury and T-helper cell liver infiltration, induces apoptosis of Con A-activated T cells, suppresses plasma levels of TNF and IFN-γ	[89]
	Inflammation-induced chronic cholestatic hepatitis at an early age, and HCC at later age (Mdr2-KO mice)		Protective	Galectin-1 is up-regulated in Mdr2-KO/B6 strain at early age	[91]
	Galectin-1-KO mice in the context of Con A-induced autoimmune hepatitis		Protective	Con A up-regulates galectin-1 in galectin-1-KO/B6 and Mdr2-KO/FVB strains. Endogenous galectin-1 selectively protects liver in the B6, but not in the FVB genetic background. It probably determines strain-specific differences in the course of chronic hepatitis and HCC development in the Mdr2-KO model	[91]
Galectin-3	NASH model	Galectin-3-KO mice	Protective	Develops NAFLD/NASH spontaneously with aging	[140,141]
		CDAA diet-induced NAFLD/NASH in galectin-3-KO mice	Protective	Galectin-3 deficiency causes more severe hepatic injury and alterations in the expression of genes associated with carcinogenesis and lipid metabolism	[142]
		Atherogenic diet-induced NASH in galectin-3-KO mice	Promotes disease severity	Attenuates NASH: inhibits HSC-driven fibrosis, reduces inflammatory-cell infiltration and hepatocyte apoptosis, acts as a major scavenger receptor involved in ALE/AGE uptake by the liver	[143]
	Human liver tissues		Protective	Negative expression of galectin-3 in normal hepatocytes, strong staining for galectin-3 in hepatocytes from patients with steatosis hepatitis, hepatitis, cholestasis and cirrhosis	[145]
	Acute liver failure induced by APAP- hepatotoxicity in galectin-3-KO mice		Perpetuates liver injury	In wild type mice, galectin-3 is up-regulated in liver infiltrating macrophages. In galectin-3 deficient mice the pro-inflammatory M1-type macrophages subpopulation, the classical macrophage activation markers iNOS, TNF and IL-12 and pro-inflammatory chemokines are reduced	[147,148]
	Hepatitis induced by injection of Con A in galectin-3-KO mice		Pro-inflammatory	Galectin-3 deficiency reduces the number of T lymphocytes, B lymphocytes, dendritic cells, NK and NKT cells and enhances apoptosis of mononuclear cells	[149]
	Con A-induced liver injury in wild type mice pretreated with a selective inhibitor of galectin-3 (TD139)		Pro-inflammatory	TD139 attenuates liver injury, reduces the number of CD4+ and CD8+ T cells, favors the influx of IL-10-producing CD4+ T cells in the liver, decreases serum levels of IFN-γ, IL-17 and IL-4	[149]
Galectin-9	Blockade of the TIM-3/galectin-9 pathway using an anti-TIM-3 or anti-galectin-9 mAb in a context of liver IRI		Protective	Blockade of the TIM-3/galectin-9 pathway increases hepatocellular damage, local neutrophil infiltration, T cell and macrophage accumulation and liver cell apoptosis. Increases IFN-γ production by Con A-stimulated spleen T cells and augmented TNF and IL-6 production by Con A-stimulated macrophages/T cells	[190]
	Single injection of galectin-9 in the murine model of liver injury induced by Con A		Protective	Eliminates activated CD4+ effector T cells, prevents the synthesis and/or release of proinflammatory cytokine	[191]
	Mouse model of diet-induced NAFLD treated with galectin-9		Limits the inflammatory response	Induces apoptosis of NKT cells, also interacts with TIM-3-expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation	[195]

ALE/AGE: Advanced lipoxidation and glycation end products; APAP: Acetaminophen; CDAA: Choline-deficient L-amino-acid; Con A: Concanavalin A; HSC: Hepatic stellate cells; IFN-γ: Interferon γ; IL: Interleukin; iNOS: Inducible isoform nitric oxide synthase; IRI: Ischemia and reperfusion injury; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; NK: Natural killer; NKT: NK T cells; TIM-3: T-cell immunoglobulin mucin domain 3; TNF: Tumor necrosis factor; HCC: Hepatocellular carcinoma; KO: Knockout.

Table 3 Galectins in fibrosis-related liver pathologies

Galectin Member	Expression	Function and/or effect	Model	Ref.
Galectin-1	Over-expressed in activated HSCs	Induces proliferation of HSCs via ERK 1/2 through CRD domain	HSCs activated in vitro (cultured on plastic for several days) and in vivo (isolated form rats treated with CCl4 or with bile duct ligation)	[93,94]
	Positive in ICC cells, intracellular expression and secretion	Correlates with histologic dedifferentiation, vascular invasion, and lymph node metastasis	ICC tissue samples, CCKS1 cholangiocarcinoma cell line	[96]
Galectin-3	Over-expressed in activated HSCs	Induces proliferation via ERK 1/2 involving PKA and PKC pathwaysDependent on CRD domain	HSCs activated in vitro (cultured on plastic for several days) and in vivo (isolated form rats treated with bile duct ligation)	[94]
		Intracellular Gal3 is required for activation of HSCs via TGF-β	HSCs activated in vivo (isolated form rats treated with CCl4)	[132]
		Extracellular Gal3 required for activation of HSCs. Integrin and CRD dependent effect	HSCs activated in vivo (isolated from rats with bile duct ligation)	[134]
		NFκβ induces expression and secretion of Gal3 in activated HSCs
	Up-regulated in injured/cirrhotic hepatocytes	Poor liver function	Human fibrotic liver samples and extracts from rats treated with CCl4	[124,133,136]
		Related to the preneoplastic and early neoplastic stages of ICC	ICC tissue samples	[96,137]
	Positive in ICC cells	Intracellular expression is associated withanti-apoptotic activity and resistance to chemotherapeutic agents	ICC cell lines	[138]

HSC: Hepatic stellate cells; CRD: Carbohydrate recognition domain; ERK: Extracellular signal-regulated kinase; ICC: Intrahepatic cholangiocarcinoma; PKA: Protein kinase A; PKC: Protein kinase C.