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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 7 of 18

then the complex is targeted to the nucleus, where it interacts with c-Myc. This interaction stabilizes c-Myc
and enhances c-Myc-driven ribosomal biogenesis and HCC cell growth. Interestingly, HBx viral protein
has been shown to interplay with several of these p53R249S partners. HBx is able to increase CDK4 activity
and also to interact with Pin1 and thus enhances HBV-related hepatocarcinogenesis [63,64] . The identification
of this CDK4-p53R249S-PIN1-c-Myc pathway could explain the high frequency of p53R249S mutant in
HCC associated with HBV chronic infection and its low frequency in other tumor types. Moreover, the
ability of p53R249S to increase c-Myc activity allows its classification among the GOF mutants, at least in
the particular context of HCC.

ADDITIONAL MECHANISMS RESPONSIBLE FOR P53 FUNCTIONAL LOSS IN HEPATOCELLULAR
CARCINOMA
In North America and Europe, the TP53 mutation rate in HCC is around 25%, meaning that the majority
of HCC cells express the wild-type form. This indicates that mechanisms other than genetic inactivation
must ensure the abrogation of wtp53 tumor suppressor functions. Several viral (SV40 LargeT Ag, Ad12
E1B, HPV16-18 E6, HBx) and cellular proteins have been reported to be able to inactivate wtp53 by
direct interaction, possibly followed by degradation [65-68] , the prototype being MDM2, a direct p53-target
gene. MDM2 protein is an E3 ubiquitin ligase able to bind p53 and to drive the complex to proteasomal
[69]
degradation . In physiological conditions, MDM2 is the main regulator of p53 intracellular levels, but it
has been found to be overexpressed, mainly in sarcomas, but also in HCC (around 25% positivity), leading
to wtp53 loss in the tumor cells [70,71] .

In addition to MDM2, 18 other E3 ubiquitin ligases leading to p53 proteasome-dependent degradation
[72]
have been reported . Some of them are of particular interest, since their expression has been found to
be altered in HCCs. PIRH2 overexpression in human HCCs is associated with a worse prognosis , while
[73]
COP1 silencing results in the inhibition of proliferation and the induction of apoptosis in human HCC
cells, as well as in the suppression of tumor growth in mouse liver . Notably, PIRH2 and COP1, like
[74]
MDM2, are encoded by genes inducible by p53 and, although they act independently, all participate in the
autoregulatory feedback loop that controls p53 function [75,76] . RING1 and CUL4A E3 ubiquitin ligases are
also overexpressed in HCCs [77,78] and play a role in stem cell maintenance. RING1, by activating the Wnt/
[79]
β-catenin pathway, promotes the transformation of hepatic progenitor cells into CSCs . The CUL4A/
DDB1 complex that plays a key role in HBV replication controls embryonic and hematopoietic stem
cell differentiation and homeostasis . Although each of these ubiquitin ligases can, in principle, favor
[80]
hepatocarcinogenesis by inducing wtp53 degradation, their contribution to HCC development is not
known and the prevalent mechanism of hepatocarcinogenesis in the absence of TP53 mutations in human
HCCs may be, according to the data available so far, the overexpression of ΔNp73 (see below).

TRUNCATED MEMBERS OF THE P53 FAMILY ACT AS FUNCTIONAL INHIBITORS OF WTP53
The N-terminal truncated isoforms (ΔTA or ΔN) of p53, p63 and p73, generated by the use of internal
promoters (P2), alternative splicing of the first exons or the use of alternative translation start sites, exert a
DNE on TA isoforms [18,19,81] . Two major mechanisms underlie the DNE of ΔTA/ΔN p53, p63 and p73 [Figure 3].
The first is a direct competition of ΔN-tetramers with p53, TAp63 and TAp73 on the same p53REs and the
consequent inhibition of p53/TAp73-mediated activation (right middle and lower panels). The second is
the oligomerization with TA proteins to form transcriptionally ineffective heterocomplexes (right upper
panel). Notably, since the oligomerization domains are only partially conserved, p73 and p63 form hetero-
[82]
oligomers with each other but not, or to a very limited extent, with p53 .

The mechanisms responsible for the differential expression of TA and ΔN isoforms in the different tissues
and pathophysiological conditions are far from being fully elucidated. Several signaling and/or oncogenic