Biomarkers for hepatocellular carcinoma based on body fluids and feces

Table 1 The major values of circulating tumor cells and extracellular vesicles for management of hepatocellular carcinoma

Biomarkers	Functions	Ref.	Notes
CTCs	Recurrence prediction	Chen et al[47], Wang et al[48] and Zhou et al[49]	A close relationship between postoperative CTC levels and early recurrence in HCC patients after liver transplantation or partial hepatectomy was revealed
	Recurrence prediction	Qi et al[50]	A preoperative CTC count ≥ 16 and a mesenchymal-CTC percentage ≥ 2% were significant risk factors associated with early HCC recurrence, multi-intrahepatic recurrence, and lung metastasis
	Prognostic evaluation	Shen et al[51]	An EpCAM-positive CTC count detected before therapy could predict poor survival of patients with HCC
	Prognostic evaluation	Hamaoka et al[52]	A GPC3-positive CTC count detected before therapy could predict poor survival of patients with HCC
	Prognostic evaluation	Luo et al[53]	The presence of CTC-associated white blood cell clusters detected before therapy could predict poor survival of patients with HCC
	Diagnosis/management	Guo et al[54]	A CTC panel including four putative stem cell biomarkers showed great potential in HCC diagnosis, outcome prediction, as well as treatment response evaluation
	Monitoring response to therapy	Rau et al[55]	Changes in some CTCs could reflect treatment response to regional therapies, particularly helpful in monitoring AFP-negative HCCs
EVs	Therapeutic targets	Son et al[66]	A new strategy of transferring the sodium/iodide symporter protein to cells via EVs was explored to increase iodine uptake and cytotoxicity in the HCC cells
		Pomatto et al[67]	Mild electroporation allowed a more efficient and functional miRNA encapsulation in EVs and achieved better protection of antitumor miRNAs from RNase degradation
		Liu et al[68] and Wang et al[69]	Hepatic stellate cell-derived EVs loaded with therapeutic nucleic acids such as miR-30a-3p and miR-335-5p decelerated the progress of HCC by directly regulating targets
		Lu et al[72]	AFP-enriched exosomes derived from dendritic cells allowed the stimulation of antitumor immune responses in autochthonous HCC mouse models in eliciting tumor regression

AFP: Alpha-fetoprotein; HCC: Hepatocellular carcinoma; CTC: Circulating tumor cell; EpCAM: Epithelial cell adhesion molecule; GPC3: Glypican-3; HBV: Hepatitis B virus; EV: Extracellular vesicles.

Table 2 Multiple potential urinary biomarkers used for hepatocellular carcinoma prevention, diagnosis, and recurrence prediction

Function	Ref.	Biomarkers
HCC prevention	Wu et al[73]	8-oxodeoxyguanosine
	Wu et al[74]	15-F2t-isoprostane
	Yuan et al[75]	8-epi-prostaglandin F2α
	Mahmoud et al[76]	8-hydroxy-deoxyguanosine
Detection/diagnosis	Abdalla and Haj-Ahmad[77]	DJ-1, Chromatin Assembly Factor-1, Heat Shock Protein 60
	Zhan et al[78]	AFP and orosomucoid 1
	Zhao et al[79]	7 urinary protein features
	Ladep et al[80]	A panel including inosine, indole-3-acetate, galactose, and N-acetylated amino acid
	Abdalla and Haj-Ahmad[83]	miR-618 and miR-650
	Jeng et al[84]	Adenosine, cytidine, and inosine
Recurrence prediction	Kikuchi et al[85]	Trypsin inhibitor
	Ye et al[86]	Ethanolamine, lactic acid, acotinic acid, phenylalanine and ribose

HCC: Hepatocellular carcinoma; AFP: Alpha-fetoprotein.

Table 3 The diagnostic, prognostic, and therapeutic values of gut microbiota

Functions	Ref.	Notes
Diagnosis	Ren et al[89]	The selected panel of 30 optimal gut microbial markers showed a powerful diagnostic performance for early HCC, achieving an AUC of 80.64% between 75 early HCC and 105 non-HCC subjects
	Lapidot et al[90]	The environmental factors leading to fatty liver, consumption of artificial sweeteners, and high-sugar foods were significantly associated with changes in the microbiota of cirrhotic patients with HCC
Monitoring response to therapy	Zheng et al[91]	Gut microbiota could influence the response to immunotherapy in patients with HCC
Prognostic evaluation	Huang et al[92]	Six microbial biomarkers related to tumor immune microenvironment or bile acid metabolism could predict clinical outcome
	Iida et al[93]	The intestinal anaerobic bacteria including Blautia were associated with more favorable prognosis in liver cancer patients after chemotherapy, but usage of anti-anaerobic drugs with poorer prognosis
Therapeutic targets	Rattan et al[94]	The use of probiotics in murine HCC models resulted in reducing HCC development

HCC: Hepatocellular carcinoma; AUC: Area under curve.