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

The mechanism of the conversion from terminally differentiated cells that expose to oncogenic factors into
CSCs remains largely uninvestigated. Dhar et al. explained this phenomenon that CD44 could activate
[81]
AKT to induce Mdm2 phosphorylation nuclear translocation, which terminated the p53 DNA-damage
surveillance. This process enables DNA- sequestered hepatocytes to avoid p53-induced apoptosis and to
respond to proliferation-related signals that promotes daughter cells transfer to HCC progenitors. CD44s,
regulated by the YAP1/TEAD axis, can positively modulate the YAP1 expression along with its target genes
through the PI3K/Akt pathway in HCC. This processes composed a feedback loop consisting of CD44s and
YAP1, promoting HCC tumorigenesis by regulating cell proliferation and invasion during . Kopanja et al.
[82]
[83]
find that FoxM1 expression level is associated with CD44 expression, suggesting that FoxM1 is required for
the expression of CD44 in HCC cells. In liver cancer, anti-miR-27a/QD-HA-PEI exhibit effective anti-cancer
effects in vitro and in vivo via down-regulation of FOXO1 and PPAR-γ . Galunisertib (LY2157299), a selective
[84]
ATP-mimetic TGF-β inhibitor, can effectively reduce tumor cell vitality via alleviating expression of CD44
and THY1 . INK128, an ATP-competitive mTOR inhibitor, can suppress CD44+ and sorafenib insensitive
[85]
HCC in vitro and in vivo .
[86]

CD90
In 1964, CD90 was initially named as θ antigen because it had identified in a process to develop an antileukemia
xeno-antibody in CH3 AKR strain mice . Later in 1969, θ antigen was renamed as Thy-1 since the thymus
[87]
was found to the location where precursors of T cells got mature . In the 1980s, Ades et al. isolated CD90
[88]
[89]
from MOLT-3, a human T-cell leukemia cell line, demonstrated the presence of CD90 in human. CD90 is a
25-37 kDa glycosylphosphatidylinositol-anchored glycoprotein, and a crucial modulator of multiple cellular
events, including immunologic function of promoting T cell activation and nonimmunologic functions such
as nerve regeneration, tumorigenesis, metastasis, inflammation, and fibrosis . The CD90+ LCSCs isolated
[90]
from liver cancer tissue specimens shows a strong tumorigenic potential after being implanted into nude
mice . Zhang et al. illustrated that by activating the IL6/JAK2 pathway, SHH/Gli could regulated the stem-
[91]
[4]
cell like characteristics of CD90+ LCSC. Cytotoxic drugs 5-FU or epirubicin treatment result in the generation
of CD90+ and CD105+ cells in vitro in Huh1 and Huh7 cells, which primarily have no CD90+ nor CD105+
cells . It was shown by Jia et al. that being as a closely related cause to chemoresistance, the overexpression
[93]
[92]
of ABCG2 and Oct5 was frequently enriched in CD90+/CD133+ LCSCs. Subcutaneous transplantation of
CD90+/CXCR4+ HCC cells to NOD/SCID mice are easily detected in the peripheral blood and able to develop
distal metastatic tumors . The expression of CD90+ does not overlap with the expression of EpCAM+. Gene
[94]
expression analysis shows that EpCAM+ cells display epithelial characteristics, while CD90+ cells exhibit a
vascular endothelial type of gene profile . Exosomes containing miR-125a and miR-125b derived from TAMs
[95]
mediate stem cell properties in HCC by targeting CD90 . Zhang et al. demonstrated that has 0067531
[97]
[96]
affected the biological functions of CD90+ HCC cells by regulating P13K-AKT signaling pathway. Moreover,
CD90 overexpression is shown to be associated with unfavorable prognosis . Overall, the results of present
[98]
studies have suggested that CD90 is a potential biomarker for HCC diagnosis and targeting therapy.

EpCAM
EpCAM is the first human tumour-associated antigen identified with monoclonal antibodies (mAb) ,
[99]
and also the first monoclonal antibody manufactured against for human cancer is murine mAb 17-1A
targeting EpCAM [100,101] . According to an early elaborate review about EpCAM in cancer , it is a type
[102]
I membrane protein of 314 amino acids, containing two epidermal growth factor-like domains at the
extracellular domain and 26 amino acids at intracellular domain. EpCAM is a cell surface marker expressed
in almost all the epithelial tumors . The EpCAM+ HCC cells possess CSC-like characteristics including an
[103]
enhanced self-renewal ability and differentiation potential, and are able to initiate the development of highly
tumorigenic cancer in NOD/SCID mice. EpCAM is a target gene in Wnt-β-catenin signaling pathway [5,104] .
Chemoresistance as well as stemness of EpCAM+ LCSCs are modulated by abnormal expression of CHD4 ,
[105]