Implications of biomarkers in human hepatocellular carcinoma pathogenesis and therapy

Table 1 Several important molecular-targeted therapies that inhibit the vascular endothelial growth factor/vascular endothelial growth factor receptor signaling pathways involved in hepatocellular carcinoma

Names of drug	Targeted signaling pathways	Phase/number of patients	Main side effects and prevalence	Efficiency (mo) (PFS/OS)
Sorafenib	Raf/MAPK/ERK, VEGFR-2, -3, PDGFR	II/137	Diarrhea (8%), hand-foot skin reaction (5%)	5.5/9.2[49]
Bevacizumab	VEGF/VEGFR	II/46	Hypertension (15%), thrombosis (6%), and major bleeding (11%)	6.9/12.4[52]
Sunitinib	VEGFR1, VEGFR2, PDGFR, c-KIT, FLT3, RET kinases	II/45	Fatigue (62%), diarrhea (47%), nausea (44%)	1.5/9.3[54]
Brivanib	VEGFR, FGFR	II/55	Hypertension (33.8%), proteinuria (14.7%), hemorrhage (11.8%)	2.7/10[56]
Linifanib	VEGFR and PDGFR	II/44	Hypertension (25.0%) and fatigue (13.6%)	3.7/9.7[58]
Ramucirumab	VEGFR-2	II/40	Hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%)	4.0/12[59]

VEGFR: Vascular endothelial growth factor receptor; ERK: Extracellular regulated protein kinases; MAPK: Mitogen-activated protein kinase; PDGFR: Platelet-derived growth factor receptor; FGFR: Fibroblast growth factor receptor; PFS: Progression-free survival; OS: Overall survival.

Table 2 Clinical relevance of deregulated microRNAs in hepatocellular carcinoma

Molecular alteration	miRNAs	Clinical significance
Down regulation	miR-139	Poor survival[70]
	miR-26	Shorter overall survival[82-87]
	miR-124	Gain of metastatic properties early recurrence[69]
	miR-145	Advanced tumor progression, poor prognosis[71]
	miR-199a-3p	Reduced time to recurrence[72]
	miR-199b-5p	Poor overall survival and Progression-free survival rates[72]
	miR-122	Poor prognosis[82-87]
Up regulation	miR-222	Shorter disease-free survival[73]
	miR--135	Poor prognosis worse Edmondson-Steiner grade, vein invasion, shortened overall survival and disease-free survival[74]
	miR-221	Multinodularity, reduced time to recurrence, gain of metastatic properties high tumor capsular infiltration[79]
	miR--155	Poorer recurrence-free survival and overall survival[75]
	miR--182	Intrahepatic metastasis and poor prognosis[76]
	miR- 10b	Poor prognosis[77]
	miR-17-5p	Poor prognosis[78]
	miR-21	Poor prognosis[79]

Table 3 MicroRNAs deregulated in hepatocellular carcinoma

miRNAs	Expression in HCC	Target	Involvement in cellular processes
miR-199	Down	Met, mTOR, PAK4, DDR1, caveolin-2	Proliferation, autophagy, metastasis, invasion; autophagy, drug resistance; cell growth[95]
miR-449	Down	c-Met	Proliferation; apoptosis[97]
miR-122	Down	Bcl-w, ADAM-1, Wnt-1	Apoptosis; metastasis; angiogenesis[100-102]
miR-34a	Down	c-Met; CCL22	Metastasis[103]
miR-200a	Down	HDAC4	Proliferation; metastasis[104]
miRs-let-7a, -7b, -7c, -7d, -7f-1	Down	Caspase-3, HMGA2, C-myc, Bcl-xl	Proliferation, apoptosis[112]
miR-125a, -125b	Down	MMP11, SIRT7, VEGF-A, LIN28B2, Bcl-2, Mcl-1, Bcl-w	Angiogenesis, apoptosis, metastasis, proliferation[115,116]
miR-29	Down	SPARC	Proliferation[114]
miR-224	Up	RKIP; CDC42; CDH1; PAK2; BCL-2; MAPK1; API-5	Metastasis; proliferation; apoptosis[113]
miR-519d	Up	CDKN1A/p21; PTEN; AKT3; TIMP2	Proliferation; invasion; apoptosis[109]
miR-216a	Up	TSLC1,PTEN	Tumorigenesis[107]
miR-148a	Up	PTEN	Tumorigenesis[108]
miR-21	Up	PTEN, RhoB, PDCD4	Drug resistance, metastasis[105,106]
miR-221	Up	Bmf, DDIT4, Arnt, CDKN1B/p27, CDKN1C/p57	Angiogenesis, apoptosis, proliferation[98,99]

HCC: Hepatocellular carcinoma.