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Page 8 of 18 Zhang et al. Hepatoma Res 2019;5:27 I http://dx.doi.org/10.20517/2394-5079.2019.13

have confirmed that calcium channel α2/δ1 subunit is a potential marker for CSCs in laryngeal squamous
cell carcinoma and in non-small cell lung cancer . Zhao et al. identified α2/δ1 subunit as a LCSCs
[149]
[148]
[11]
marker and developed its monoclonal antibody named 1B50-1, which had positive therapeutic effects on
HCC xenograft by eradicating LCSCs. α2/δ1 + liver cancer cells have stemness characteristics, including
the expression of stemness-related genes such as SOX2, OCT4, BMI1, and NANOG , the capability of self-
renewal, invasiveness, and to produce both α2/δ1 + and α2/δ1 - cells . Recently, Zhang et al. discovered
[11]
[150]
that miR-31 could negatively manipulate the self-renewal capability of α2/δ1 + LCSCs via sequestering ISL1,
implying a potential therapeutic strategy for directly targeting liver TICs.

OV6
1998, Roskams et al. identified that reactive ductules and intermediate hepatocyte-like cells originated
[151]
partially from differentiation and activation of progenitor cells. It has been put forward that OV6 in human
liver can help identify cells owing a progenitor stem cell-like characteristics, which has the ability to
differentiate into OV6+ ductular cells or lobular hepatocytes. OV6+ is a specific phenotype of oval cells
that has been originally identified in the livers of tumor transplanting rats, and is identified as a surface
marker of human liver progenitor cells in 2008 . In 2012, Yang et al. further demonstrated that OV6+
[152]
[12]
HCC cells not only possessed a stronger capacity to form spheroids, but also showed stronger tumorigenic
and metastatic characteristics. These results suggest that OV6+ HCC cells are highly capable of self-renewal
and forming tumors. Wnt/β-catenin signaling plays an indispensable role in the induction and expansion
of OV6+ subpopulation within tumor tissues. Thereby, OV6 is considered as an effective LCSCs surface
marker. Additionally, Yang et al. also demonstrated that overexpression of OV6 enhanced the invasive and
[12]
metastatic characteristics of HCC CSCs so that the number of OV6+ CSCs increased in patients diagnosed
with liver cancer indicated poorer clinical outcomes and prognosis.

DLK1
DLK1 has shown to be expressed in fetal liver, but scarcely expressed in neonatal and adult liver in mice
and rats . Huang et al. demonstrated that proliferation of SMMC-7721 cells was significantly enhanced
[153]
[154]
by exogenous DLK1, whereas colony-forming ability, cell growth, and tumorigenicity of Huh-7, Hep3B, and
HepG2 cells were significantly impeded by the suppression of endogenetic DLK 1 via RNA interference. It
was identified by Li et al. that the enhancing effect of DLK1 in tumourigenicity and cancer stemness could
[13]
potentially be used as a molecule target for therapies against LCSCs. DLK1+ cells have been discovered in all
17 HCC cell lines and showed a more potent capability of clonogenicity in vitro and tumorigenicity in animal
models. In addition, some stemness markers have been identified upregulated in DLK1+ Huh-7 and Hep3B
cells including NANOG, SMO, SOX2, Oct3/4, CD133, CD90, and EpCAM. The isolated DLK1+ HCC cells
are possess strong therapeutic resistance to conventional cytotoxic agents such as doxorubicin, cisplatin,
epirubicin, and 5-FU .
[155]

K19
Cytokeratin 19(K19) is a newfound CSC surface marker associated with EMT and TGFb/Smad signaling
pathway . K19 disappears from liver cells but remains in bile duct cells at the 10th differentiation week,
[14]
which is an important step in the organogenesis of liver . It has been reported that using 18F-FDGPET
[156]
and CYFRA 21-1 can identify K19+ LCSCs in HCC. In patients with HCC, K19 expression is significantly
correlated with GLUT1 expression and FDG accumulation, and K19 regulated 18F-FDG uptake via TGFβ/
Smad signaling pathway . Besides the TGFb/Smad signaling pathway, many other signaling pathways have
[157]
been documented as well. The PDGFRα-laminin B1-K19 cascade drives tumor development at the invasive
front of HCC . Rhee et al. reported that expression of K19 in HCC is modulated by fibroblast-derived
[159]
[158]
HGF via a MET-ERK1/2-AP1 and SP1 axis. K19+ cells have high proliferation potential and doxorubicin,
5-fluorouracil and sorafenib resistance [14,160] . K19 expression exhibits strong correlation with increased