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Zhang et al. Hepatoma Res 2019;5:27 I http://dx.doi.org/10.20517/2394-5079.2019.13 Page 3 of 18

Figure 1. Acquired chemo- and radioresistance in liver cancer stem cells. Traditional chemo-/radiotherapy can induce genetic alteration in
non-stem liver cancer cells (NSLCCs) via DNA damage and cytotoxic agent intake, in order to activate cellular apoptosis. However, upon
treated with traditional chemo-/radiotherapeutic agents, liver cancer stem cells (LCSCs), can acquire chemo-/radioresistance including
an increased level of drug intake and an enhanced DNA repairing mechanism, which eventually lead to a higher survival rate of LCSC
subpopulation.

Table 1. Summary of liver cancer stem cell biomarkers and related pathways
Surface markers of LCSCs Related pathways
CD133 AKT/PKB [30] , EGFR-AKT [38] , IL-8/CXCL1 [33] , Aldehyde dehydrogenases [25] , JNK [39] , mTOR [40] , TGF-β [41,42] ,
Aurora kinase/RalA [43] , Notch1 [44] , PTEN [45] , NF-κB [45] , ZFP42/REX1 [46] , miR-150/c-Myb [47] , miR-142-
3p [48] , miR-152/KIT [49] , miR-130b/TP53INP1 [29] , miR-1246/Wnt/β-catenin [50] , LncSox4/Stat3 [58]
CD44 AKT [81] ,YAP1/TEAD [82] , anti-miR-27a/QD-HA-PEI [84] , TGFβI/ALK5 [85] , mTOR [86] , FoxM1/ROS [83]
CD90 SHH/Gli and IL6/JAK2/STAT3 [91] , ABCG2 and Oct5 [93] , miR-125a/b [96] , has 0067531 [97]
EpCAM Wnt-β-catenin [5,104] , CHD4 [105] , OSM [106] , ATRA [107] , EZH2 [108] , miR-155 [109] , miR-181 [111] , miR-216a/217/
PTEN /SMAD7 [110]
CD47 CTSS/PAR2 [6,120] , NF-κB [122] , SIRPα [119]
[7]
CD34 OCT4, SOX2, NAONG, Klf4, c-Myc, and Lin28
C-kit TGF-β/SMAD2 and c-KIT/JAK1/STAT3 [132]
CD13 TGF-β-/EMT [139]
CD24 STAT3/NANOG [10,144] , Twist2 [144]
[11]
α2δ1 OCT4, SOX2, NANOG, and BMI1 , miR-31/ISL1 [148]
OV6 Wnt/β-catenin [12]
DLK1 Nanog, SMO, SOX2, Oct3/4 [153]
K19 EMT and TGFb/Smad [14,155] , PDGFRα-laminin [156] , MET-ERK1/2-AP1 and SP1 [157]
LGR5 HGF/ Rspo1 [173] , LSD1/Prickle1/APC/β-catenin [175]

shown to be more resistant to radiotherapy and chemotherapy . Our previous study found that CD133+
[37]
[36]
cancer stem cells conferred chemoresistance caused by abnormal activation of the Akt/PKB pathway . Other
[30]
Aberrant signaling pathways related to CD133+ LCSCs have also been reported and characterized including
[33]
[38]
[39]
[40]
[25]
EGFR-AKT , IL-8/CXCL1 , aldehyde dehydrogenases , JNK , mTOR , TGF-β [41,42] , aurora kinase/RalA
pathway , Notch1 signaling pathway , PTEN signaling pathway , NF-κB signaling pathway . Recently,
[45]
[45]
[44]
[43]
our team identified ZFP42/REX1 as a key regulator of cancer stemness in CD133+ LCSCs by genome-wide
DNA methylation analysis . A panel of miRNAs that include miR-150, miR-142-3p, miR-152, miR-130b and
[46]
miR-1246 have also been found to regulate proliferation, tumorigenicity, invasion, migration and angiogenesis
in CD133+ HCC cells [29,47-50] .
In summary, aforementioned studies demonstrate that the maintenance of CD133+ LCSCs is modulated by
an intricate network of signaling pathways. Cells with varied morphological structures primarily constitute
HCC and express distinct hepatic lineage genes. Thereby, there might also be functionally different cancer
cell subpopulations that express distinct stemness-associated markers. Wilson et al. have shown that the
[51]