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Caron de Fromentel et al. Hepatoma Res 2020;6:80 I http://dx.doi.org/10.20517/2394-5079.2020.77 Page 9 of 18

by the polycomb repressor complex 2 [124] , a complex required for maintaining ES cell pluripotency
and plasticity during embryonic development [124-126] . A direct link between some p53 mutants, like
p53R248W in osteosarcoma cells, and the acquisition of CSCs features (high proliferation rate, sphere
formation, clonogenic growth, high migration and invasive ability) and increased aggressiveness has been
established [127] . Truncated forms of p53 have also been shown to favor cancer stemness. For example,
the Δ133p53β isoform enhances the expression of the pluripotency factors SOX2, OCT3/4 and NANOG,
promotes mammosphere formation and is associated with metastatic potential and chemoresistance in
breast cancer cell lines [128] . The N-terminal truncated isoforms of p63 and p73 are also involved in the
emergence and maintenance of CSCs. ΔNp63, which has been described as master regulator of normal
epithelial stem cell maintenance in stratified and glandular epithelia [129,130] , promotes stem cell properties
by activating signaling pathways, like the Wnt/FZD7 pathway in basal-like mammary cell lines [130] , or
components of the Hedgehog (Hh) pathway (SHH, PTCH1, and GLI2) and the Hh-target gene BMI1 in
mammary cell lines with a luminal-like phenotype [131] . Notably, BMI1 plays important roles in the self-
renewal of normal and CSCs [132] , as well as in the chemoresistance and survival of CSCs from several tumor
types [133] . ΔNp73 also favors CSCs properties. Its overexpression in a non-tumorigenic melanoma cell
line exerts a DNE on TAp73-mediated miR-885-5p expression, a negative regulator of the IGF1 receptor
(IGF1R) [134] , leading to an increased expression of IGF1R and, consequently, of CD133, NANOG and OCT4
and an enhanced ability to form tumors in xenografts [134] . ΔNp73 also forms complexes with Smad3/4 on
Smad binding elements, leading to the enhanced transactivation of stemness-related TGFβ-target genes [135] .
Finally, both ΔNp63 and ΔNp73 are able to enhance reprogramming by favoring the mesenchymal-
epithelial transition (MET) required during iPSCs generation [136,137] and in the case of ΔNp73, by inhibiting
wtp53 [138] .

Altogether, there is enough evidence to affirm that the truncated forms of the p53 family members and
some p53 mutants not only act as functional inhibitors of wtp53 but also exhibit new additional functions,
some of them contributing to stemness. It is more difficult, however, to define the relative contribution of
the different isoforms to the stem-related phenotype, due to their variable expression (not having discussed
the C-terminal variants), the complexity of their crosstalk and their largely redundant functions.

P53 FAMILY MEMBERS IN HCC
The expression and activities of p53 family members have been studied in normal hepatocytes and HCC
cells. In a small series of 16 cholangiocarcinomas (CCAs), p63 overexpression correlated with CK19
positivity and low tumor differentiation, whereas no expression was found in 37 HCCs [139] . Similarly, in
hepatocytes and HCC cell lines, TAp63 is barely expressed and the detection of ΔNp63, generated from
the P2 promoter, is restricted to p53-null cells [140] , because its expression is repressed by p53, as previously
reported in other cell types [141,142] . Conversely, ΔNp73 expression is activated by p53 and to a lesser extent
by TAp63 and TAp73 [141,143] . TAp73 and several p73 N-terminal truncated isoforms are highly expressed
in HCC samples, independently of the presence of wild type or mutant p53 [144,145] . The overexpression of
ΔNp73 and/or a high ΔNp73/TAp73 ratio are associated with a reduced survival in patients with HCC [146-149] .
Moreover, in patients with HCC undergoing OLT, recurrence and reduced survival were correlated with an
increased expression of ΔNp63 and ΔNp73, and a reduction of TAp63 and TAp73 expression [150] . All these
observations indicate that ΔNp73/TAp73 ratio could be a potentially relevant prognostic factor in HCC.

As already mentioned, the expression of p53 family members is highly dependent on the differentiation
state of cells. Thus, ΔNp73 is detected in proliferative immature HepaRG non-transformed bi-potent liver
cells, but not in the differentiated state [151] , whereas p53 and TAp73 are expressed in mature hepatocytes.
The presence of p53 in mature hepatocytes has been shown to play an important role in the maintenance
of their cell identity when exposed to an oncogenic stress. The expression of c-MYC at low levels is able
to induce the expression of NANOG, OCT4 and EpCAM and to increase both sphere formation and