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Page 10 of 18 Caron de Fromentel et al. Hepatoma Res 2020;6:80 I http://dx.doi.org/10.20517/2394-5079.2020.77

tumorigenicity of HCC cell lines [152] . c-Myc-induced reprogramming and the acquisition of CSCs features
are readily observed in p53-null cells but the functional inactivation of p53 is needed in cells with wtp53
alleles [152] . HCC cells in which p53 functional inactivation is achieved by genetic alteration or expression
of proteins that exert a DNE are prone to dedifferentiation if exposed to oncogenic stimuli. Similar results
have been obtained in mouse models. Tschaharganeh and colleagues have shown that in the presence
of high levels of YAP, an oncogene overexpressed in human HCC and CCA [153] , tp53 deletion in mature
hepatocytes facilitates their dedifferentiation in vivo, the emergence of progenitor tumor cells with high
NESTIN expression and the development of tumors sharing HCC and CCA characteristics [154] . NESTIN
was required for the dedifferentiation and malignant expansion of p53-deficient cells and the activation
of Wnt or Notch pathways in the p53-null progenitor tumors drive the development of HCC and CCA,
respectively. NESTIN was also overexpressed in 17% of human HCCs and 40% of CCAs, associated
with a reduced survival and the presence of mutations or LOH in the TP53 gene [154] . Altogether, these
results suggest that in mature liver cells the p53-mediated inhibition of NESTIN restricts plasticity and
tumorigenesis in response to oncogene activation.

LIVER CSCS AND THE CROSSTALK BETWEEN NANOG, IGF1R AND THE P53 FAMILY
Cancer tissues contain subpopulations of cells known as stem-like TICs (sl-TICs or CSCs) that have been
identified as key drivers of tumor growth and malignant progression with drug resistance. Liver CSCs are
bi-potent and give rise to two different lineage types, HCC and CCA. Indeed, combined hepatocellular-
cholangiocarcinomas (cHCC-CCAs) with both hepatocytic and cholangiocytic phenotypes account for 1%
to 5% of all primary liver cancers [155] , and about one third of HCCs express progenitor cell markers such as
CK7 and CK19 [156] , suggesting that at least a portion of HCC cells have intermediate characteristics between
the bi-potent hepatic progenitor cells (HPCs) and differentiated mature hepatocytes [157,158] . The origin of
liver CSCs and liver cancer cells is still controversial [159] and there is evidence for both their derivation from
HPCs chronically activated by the persistent intrahepatic inflammation sustained by chronic HBV, HDV
and HCV infections, alcohol consumption and metabolic disorders [160] and the dedifferentiation of mature
hepatocytes that acquire the expression of stem-related genes when exposed to inflammatory cytokines,
lipid overload or epigenetic reprogramming [161-163] [Figure 4A].

p53 has been shown to repress many key transcription regulators, such as Oct4, Nanog, Sox2, Zic3,
Jmjd1c, Esrrb, Tcfcp2l1, Utf1, n-Myc, c-Myc, and Prdm14 in mouse ES cells [164,165] . Among them, Nanog
is of particular interest with respect to the p53 family in the context of HCC development. Nanog is
overexpressed in about 30% of HCCs as shown by immunohistochemistry [166-168] , regulates the expression
of genes involved in mitochondrial metabolic pathways [169] , promotes CSC properties [169] and enhances
resistance to drugs, such as sorafenib or cisplatin, as well as tumor invasion and metastasis [169,170] .

The wtp53 represses NANOG expression either by direct binding to the Nanog promoter in mouse
cells [115,164] or by transactivating miR34a-c, a direct p53-target gene that in turn represses NANOG [171] in
human cells [172] . In a recent study, Liu and colleagues have shown that the enhanced mitophagy observed
in HCCs increases p53 localization at the mitochondrial membrane [173-176] and leads to its subsequent
degradation. In contrast, when mitophagy is impaired, mitochondrial p53 is phosphorylated by Pink1
and translocated into the nucleus, where it represses NANOG expression resulting in a decrease of liver
CSCs [176,177] .

Two p53 family isoforms are able to exert a DNE on p53 and TAp73 regulation of NANOG. Δ40p53,
by titrating full-length p53, regulates the switch from pluripotency to differentiation by increasing
the expression of Nanog and Igf1R in mouse ES cells [178] and ΔNp73, as already mentioned, interferes
with TAp73 in the regulation of IGF1R expression in human melanoma cells [134] . Furthermore, we and
others demonstrated that ΔNp73 transactivates NANOG expression independently of p53 [138,179] . The