Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials

Table 3 Some secreted factors from cellular components of tumor microenvironment and their contribution to hepatocellular carcinoma prognosis

Molecule	Molecular category	Biological function	Expression in human HCC	Clinico-pathological indications	Target for therapy	Ref.
Interleukin-4	Cytokine	Alternative activation of macrophages into M2 cells	Over-expressed (elevated level in serum)	Associated with extrahepatic metastasis	Not presented	[108]
TGF-β1	Multifunctional cytokine	Proto-oncogene/tumor suppressor	Over-expressed (elevated level in serum)	Decreased overall survival, increased risk of metastasis and recurrence, positively correlated with vascular invasion, higher PVT, higher overall invasiveness	Potential	[123]
FGF19	Growth factor	Activation of mitogen-activated protein kinase; activation of Wnt/β-catenin pathway	Over-expressed in tissue	Decreased disease-free and overall survival, increased risk of metastasis, positively correlated with vascular invasion	Potential	[117]
Fox C1	FOX transcription factor family member	Induction of EMT, promotion of epithelial cell migration via inhibition of E-Cadherin transcription through transactivation of SNAI1 expression	Over-expressed in tissue	Increased risk of metastasis and recurrence, increased tumor size and number, poorer tumor differentiation, poorer TNM stage, higher vascular invasion	Potential	[130,131]
Lcn2	Member of lipocalin protein family	Inhibition of epithelial-to-mesenchymal transition; suppression of JNK and PI3K/Akt signaling pathways, down regulation of Twist1	Over-expressed in tissue	Positively correlated with poor prognosis and high risk HCC, decreased overall survival, however, elevated levels of Lcn2 is correlated with the inhibition of EMT in vitro and in vivo	Not presented	[134,135]
uPA	Serine protease	Plasminogen activation, extracellular proteolytic activity	Over-expressed in tissue	Decreased disease-free and overall survival, increased HCC invasion, poorer pathological grade	Potential	[144,146]
uPAR	Urokinase receptor	ECM degradation, migration, invasion and metastasis	Over-expressed in tissue	Decreased disease-free and overall survival, higher risk of HCC invasion, portal cancer embolus and tumor metastasis, poorer tumor cell differentiation	Potential	[145,146]
PAI-1	Protease inhibitor	Regulating extracellular matrix degradation	Over-expressed in tissue	Decreased disease-free and overall survival, increased risk of metastasis and recurrence, increased regional invasion, poorer pathological grade	Not presented	[144,146]
VEGF	Growth factor	Regulation of vascularization and angiogenesis	Over-expressed in tissue, elevated level in serum	Poorer overall survival, increased risk of metastasis and recurrence, higher vascular invasion	Potential	[156]
HIF-1α	Subunit of HIF-1 transcription factor	Activating the transcription of a variety of genes involved in angiogenesis, survival pathways, immune evasion, invasion, and metastasis	Over-expressed in tissue	Decreased disease-free (and overall) survival, increased risk of metastasis, higher vascular invasion	Potential	[162,163]

PVT: Portal vein thrombosis; EMT: Epithelial-to-mesenchymal transition; TNM: Tumor node metastasis; FGF19: Fibroblast growth factor 19; Fox C1: Forkhead box C1; Lcn2: Lipocalin-2; uPA: Urokinase plasminogen activator; uPAR: Urokinase plasminogen activator receptor; PAI-1: Plasminogen activator inhibitor type-1; VEGF: Vascular endothelial growth factor; HIF-1α: Hypoxia-inducible factor-1α.