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C-kit
C-kit, also named as stem cell factor receptor, is a receptor protein of transmembrane type III with intrinsic
tyrosine kinase activities to generate human embryonic stem cells. Besides having been used to identify
human hematopoietic progenitor cells or hepatic stem cells, c-kit also is capable to sustain the stem cells in an
undifferentiated state. The presence of c-kit on HCC cell lines suggests that stem cell factor (SCF) have been
considered to play an indispensable role in the manipulation of the proliferative capability of liver cancer
[132]
[8]
cells . Fujio et al. demonstrated that C-kit could be an important factor in the receptor systems, a growth
factor related to the biological functions of liver stem cells and the development of bile ducts. It has been
reported that TGF-β/SMAD2 signaling pathway mediates the expression of the c-KIT receptor ligand
[133]
in a transcriptional level by activating c-KIT/JAK1/STAT3 signaling pathway. SCF activates TGF-β1 ligand
expression through STAT3, thereby result in a positive feedback loop between TGF-β/SMAD and SCF/c-KIT
signaling pathway. The signaling network attenuates TGF-β–mediated cell cycle arrest and activates tumor
[133]
cell to into proliferation, epithelial-to-mesenchymal-transition, migration, and invasion . Blockade of
C-kit in late cirrhosis might restore TGF-β inhibitory effect on normal liver stem cells and prevent initiation
and progression of HCC . The expression of C-kit is significantly higher in liver cancer patients with
[134]
advanced clinical stage and is an independent poor prognostic factor of DFS in HCC patients .
[135]

CD13
CD13, also referred as aminopeptidase N, is a membranous glycoprotein that has been used to identify
leukemia or lymphoma cells . CD13 plays vital roles in cancer progression including cell proliferation,
[136]
invasion, and angiogenesis [137-139] . Nagano et al. demonstrated that CD13 is a surface marker of CSCs
[140]
in human liver cancer and may have promising therapeutic potentials. It was found by Haraguchi et al. [9]
that CD13 attenuated ROS-induced DNA injury after chemo/radiation treatment and protected cells from
apoptosis. They also found that ubenimex, a CD13 inhibitor, alleviated oncogenic and self-renewal ability
of CSCs and suppressed CD13+ tumor growth with co-treatment of 5-FU. Kim et al. reported that
[141]
upregulated CD13 expression was associated with TGF-β-induced EMT-like process, which prevents further
increasing of ROS level as well as the induction of apoptosis, supporting the survival of CD13+ CSCs in liver
cancer cells. It was also shown by Yamashita et al. that ubenimex synergistically enhanced the antitumor
[142]
effects of a chemotherapy regimen composed of 5-FU, CDDP and DXR on HCC cells, and the functions of
ubenimex were associated with enhanced intracellular ROS levels.

CD24
CD24 is a glycosylated and mucin-like cell surface glycoprotein with relatively high expression in stem/
progenitor cells and related to formation and development of CSCs isolated from breast, colon, ovary,
[145]
pancreas [143,144] . Huang et al. firstly cloned the full-length CD24 cDNA sequence from human HCC cells
and identified that CD24 mRNA overexpression was associated with p53 mutation and tumor differentiation.
[10]
Lee et al. reported CD24 as a surface marker of LCSCs. They also documented that CD24 was upregulated
[10]
in chemoresistant tumors after cisplatin treatment in immunodeficient mice model. Significantly, CD24
expression largely overlaps with expression of CD133 and EpCAM in HCC . CD24+ HCC cells have a great
[10]
impact on clinical prognosis of patients, and play a vital role in self-renewal, differentiation, maintenance,
and metastasis of tumors . Self-renewal and tumor initiating behavior of CD24+ LCSCs is regulated by
[10]
STAT3-mediated NANOG regulation . It was demonstrated by Liu et al. that the pathway of Twist2-
[146]
[10]
CD24-STAT3-NANOG was crucial to the regulation of self-renewal of CD24+ LCSCs.
α2δ1
In 2010, García et al. reported that when the expression of calcium channel α2δ1 subunit was inhibited,
[147]
migration, adhesion as well as spreading of myoblasts were impaired, whereas the L-type calcium maintained
unaffected, suggesting a newfound function of the α2/δ1 subunit in extracellular signaling. Later studies