Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials

Table 2 Micro-interfering RNA, miRBir and epigenetic markers of human hepatocellular carcinoma progression and poor prognosis

Molecule	Molecular category	Biological function	Expression levels in human HCC tissue	Clinical pathological indications	Target for therapy	Ref.
miRNA-18b	Belongs to Oncomir-1 or miR17-92 cluster	Involved in embryogenesis and spermatogenesis	Over-expressed	Poor differentiated HCC, high levels positively correlate with lower survival time	Potential	[70]
miRNA-372	Oncomir	Not well defined: it can act as an oncomir or as an anti-oncomir depending on the malignancy	Over-expressed	High levels positively correlate with advance TNM stage, shorter recurrence-free survival and overall survival	Potential	[74]
miRNA-650	Oncomir	Targets protein involved in cell proliferation and survival	Over-expressed	Higher levels in less than 60-year-old patients; levels positively correlate with HCC differentiation status	Potential	[75,76]
miRNA-100	Tumor suppressor	Regulates cell differentiation and survival	Down-regulated	Levels negatively correlate with tumor grade, metastasis and recurrence	Potential	[77]
miRNA-132	Tumor suppressor	Involved in the repression and control of inflammation and in neuronal morphogenesis	In HBV-HCC down-modulated by HBx protein causing promoter methylation	Levels of miR-132 inversely correlate with those of HBx in HBV-HCC patients. Early diagnosis of HBV-HCC	Potential	[80]
Ago2	Belongs to eIF2C/AGO subfamily	One of the effectors of RNA interference either at initiation or elongation phases, endowed with PIWI domain (endonuclease activity)	Overexpressed (mRNA and protein levels) and gene amplification	Can signed metastasis	No data	[83]
Dicer	Belongs to the RNaseIII family	Cleaves double-stranded RNA and pre-miRNA in the short (20-25 nt) active miRNA	Down-regulated	Shorter recurrence-free survival time	No data	[84]
TFPI2 gene	Member of the Kunitz-type serine protease inhibitors gene	The encoded protein inhibits plasmin-and trypsin-mediated activation of matrix metalloproteinases.	Up-regulation of gene promoter methylation (HCC tissues and serum)	TFPI2 methylation levels positively correlate with high grade TNM, improved detection of HCC in patients with AFP levels less than 400 μg/L	No data	[87]
Ten-eleven translocation protein 1 gene	Member of the TET family of methylcytosine dioxygenase enzymes gene	The encoded protein convert 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) in various embryonic and adult tissues	Up-regulation of promoter methylation	Low levels of TET 1 and 5hmC relates to shorter overall survival	No data	[89]
MAT1A, MAT2A genes	Member of the SAM synthesizing isozymes genes	The encoded enzymes are essential to SAM biosynthesis. MAT1A is expressed in mature liver, whereas MAT2A is expressed by fetal liver, extrahepatic tissues or in HCC.	Up-regulation of MAT1A promoter methylation and down-regulation of MAT2A promoter methylation	Based on in cell culture and animal models studies, decreased MAT1A/MAT2A expression ratio has been proposed as s poor prognostic factor in HCC patients	No data	[90]

TFPI2: Tissue factor pathway inhibitor-2; Ago2: Argonaute-2; MAT1A: Methionine adenosyltransferase; HCC: Hepatocellular carcinoma; HBx: Hepatitis B virus x; SAM: S-adenosylmethionine.