Page 943 - Read Online

Page 12 of 18 Caron de Fromentel et al. Hepatoma Res 2020;6:80 I http://dx.doi.org/10.20517/2394-5079.2020.77

The characterization of how this axis is regulated in the viral and metabolic inflammatory chronic liver
diseases that precede HCC development might also help to develop new biomarkers for risk-stratification
and new preventive strategies.

The identification of at least three main mechanisms of wtp53 inactivation in HCCs may have therapeutic
implications and lead to new strategies for treatment personalization. Besides p53-based gene therapy
approaches, there are very few reports of drugs targeting the p53 family in HCC, either in preclinical
or clinical settings. PRIMA-1 (p53 Reactivation and Induction of Massive Apoptosis), a small molecule
capable of restoring a wild-type activity in some p53 mutants, has been shown to slow down tumor growth
in immunocompromised mice xenografted with p53R249S-expressing human cells [181] . Therefore, it might
be valuable to test the potential of PRIMA-Met (an improved version of PRIMA-1) and MIRA-1 (mutant
p53-dependent induction of rapid apoptosis), a small molecule targeting p53 structurally distinct from
PRIMA-1 [182] , to reactivate wtp53 functions in HCCs with p53 mutants, or of Nutlins to counteract MDM2-
mediated degradation of wtp53 [183] . IFNa has been shown to inhibit the expression of ΔNp73 by inducing
chromatin remodeling at the P2p73 promoter and increasing apoptosis of human HCC cells [184] . These
results provide a proof of concept of the possibility to target the third mechanism of wtp53 inactivation
frequently engaged in HCCs, i.e., the DNE of N-terminal truncated members of the p53 family. However,
IFNa has no indication in current HCC treatment algorithms and the identification of potent and selective
drugs capable to target ΔNp73 expression might prove of value to increase HCC chemosensitivity and to
enhance tumor and cancer stem cells apoptosis, either alone or in combination with TKIs.

DECLARATIONS
Acknowledgments
We thank Mirjam Zeisel and Giovanni Blandino for critical reading of the manuscript.

Authors’ contributions
Researched public databases for TP53 mutations: Caron de Fromentel C
Designed and wrote the manuscript: Caron de Fromentel C, Levrero M

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by grants from «Agence Nationale pour la Recherche sur le SIDA et les hepatites
virales» (ANRS) (ECTZ117561) to Levrero M, from the Agence Nationale de la Recherche (ANR@
TRACTION) to Levrero M; from the EU project (667273 HEP-CAR) to Levrero M; from the Ligue
Nationale Contre le Cancer, Coordination Auvergne-Rhône-Alpes & Saône-et-Loire to Caron de Fromentel
C and Levrero M.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.