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Page 6 of 18 Zhang et al. Hepatoma Res 2019;5:27 I http://dx.doi.org/10.20517/2394-5079.2019.13

OSM , ATRA , EZH2 . A group of microRNAs including miR-181, miR-155, miR-181, miR-216a/217
[106]
[108]
[107]
have been found involved in regulating stemness of EpCAM+ HCC cells [109-111] . Patients with EpCAM+/
AFP+ HCC have higher frequency of portal vein invasion and significantly shorter survival than EpCAM-/
AFP- HCC patients . Chen et al. proposed a novel EpCAM-antibody-labeled polymer in nano-vesicles
[112]
[113]
for cancer stem cells-targeted drug and siRNA and displayed higher tumor selectivity and killing efficacy. A
recent study revealed that metformin decreased both the EpCAM+ HCC cells abundance and self-renewal
capability . Babaei et al. reported that EpCAM targeted nanoparticles of PEG-Au@Si-5-FU exhibited
[114]
[115]
higher cytotoxicity than nontargeted PEG-Au@Si-5-FU in 2D and 3D HepG2 cell cultures. Many EpCAM
antibodies are currently available to treat patients with EpCAM+ malignant ascites in preclinical and clinical
trials including edrecolomab, adecatumumab, MT110 and catumaxomab .
[116]
CD47
CD47 is firstly discovered in 1992 as a surface protein that is frequently expressed in ovarian carcinoma .
[117]
Later studies have exhibited that CD47 is a highly expressed transmembrane protein with various
functions [118,119] . Lee et al. identified that CD47 was preferentially expressed in liver TICs, which result in
[6]
cancer development, self-renewal, metastasis and chemoresistance and significantly influence the clinical
prognosis of patients. CD47+ HCC cells preferentially secret cathepsin S (CTSS), which manipulates liver
TICs through the CTSS/protease-activated receptor 2 (PAR2) loop. Suppression of CD47 by morpholino
decreases HCC viability and exerts a chemo-sensitization effect through blockade of CTSS/PAR2 signaling
pathway [6,120] . Increased CD47 expression level has been considered as a negative prognostic factor for a
wide variety of cancer [118,121] . Lee et al. unraveled that CD47 expression was enriched on CD133+/CD24+
[6]
TICs isolated from a HCC cell line and was increased by serial passage in the presence of doxorubicin and
cisplatin, and high CD47 expression conferred chemoresistance and increased the stemness characteristics
of TICs. CD47 blockade or down-regulation suppresses HCC development and elevated sensitivity to
chemotherapeutic drugs such as sorafenib [6,122-124] , while NF‐κB‐mediated CD47 up‐regulation enhances
sorafenib resistance . Importantly, not only being considered as a LCSC surface marker, expression of CD47
[122]
is also involved in innate immune response . CD47 is a ligand for signal regulatory protein-α (SIRPα),
[123]
which expressed on macrophages and dendritic cells . After binding CD47, SIRPα activates a signaling
[125]
cascade that leads to the inhibition of phagocytosis . Macrophage phagocytosis of HCC cells is enhanced
[119]
after treatment with CD47 antibodies (CD47mAbs) that impede CD47 binding to SIRPα [118,126] . Treatment
to mice with tumor burden with antibodies that blockade CD47 signaling can produce intensive tumor
regression when used solely or integrated with existing therapeutic strategies [118,121,127,128] and humanized
CD47 antibodies have recently entered human clinical trials (NCT02678338, NCT03717103, NCT03763149,
NCT02216409, NCT02367196).

CD34
Park et al. identified CD34 + as a newfound LCSC surface marker. SOX2 is one of the vital factors maintaining
[7]
CD34+ LCSC stemness before colonization, and OCT4, SOX2, NAONG, Klf4, c-Myc, and Lin28 are supposed
to be associated with stemness maintenance of CD34 + LCSC on feeder cells . Park et al. found that CD34+
[7]
[129]
LCSCs possessed stemness characteristics and three types of liver carcinomas were directly produced from
CD34+ PLC/PRF/5 hepatoma cells (PLC): hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), as well
as combined hepatocellular cholangiocarcinoma (CHCs). CD34+ PLCs that express OV6 and their progeny
OV6+ cells primarily produce CHC and CC, suggesting that the OV6+ antigen is correlated with human CHC
and CC . Crosby et al. addressed that c-kit+ or CD34+ liver cancer cells had the potential to transfer to
[130]
[129]
biliary epithelial cell lineage and might represent biliary epithelial stem cells. Zeng et al. demonstrated
[131]
that CD34+ LCSCs and xenografts generated by CD34+ LCSCs exhibited a blended phenotypes, coexpressed
stemness and myelomonocytic cell markers. CD34+ LCSCs are often coexpressed with CD45, suggests that
the origin appears to be from a hematopoietic precursor, which illuminate a comprehensive understanding of
the molecular mechanism of how LCSCs are originated and developed .
[131]