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Page 8 of 18 Caron de Fromentel et al. Hepatoma Res 2020;6:80 I http://dx.doi.org/10.20517/2394-5079.2020.77

pathways affect TA- and/or ΔN-p73 levels by affecting transcription or protein stability. TAp73 isoform
transcription from the P1 promoter is primarily driven by E2F1 [83-88] , but its activity can be also modulated
[89]
[90]
[91]
by other factors such as C-EBPa , ZEB and Ying Yang 1 (YY1) . The regulation of the P2 promoter
is much less clear. Notably, both p53 and TAp73 bind the internal P2 promoter of TP73, activate the
transcription of P2 ΔNp73 isoforms to create a negative feedback loop between ΔNp73 and p53/TAp73 that
may self-restrict their transcriptional activities [92-95] .
The ratio between ΔN- and TA isoforms has been shown to determine the net effect and, in the case of p73,
to predict the effectiveness of chemotherapy [96-98] . The TA pro-oncogenic role of dominant negative ΔTA/
ΔN p53, p63 and p73 is supported by several observations. ΔNp73 overexpression in fibroblasts increases
[99]
their colony formation capacity and cooperates with RAS, c-Myc and E1A in promoting transformation
and tumorigenicity [21,100] . In melanoma xenografts ΔNp73 expression is associated with upregulation of
Slug, downregulation of the actin binding protein EPLIN, activation of the IGF1R-AKT/STAT3 pathway,
loss of E-cadherin and a higher ability to invade and metastasize [101] . Notably, 83% of 12-20 month-old
transgenic mice expressing ΔNp73 under the control of the albumin promoter develop HCC, confirming
the oncogenic potential of ΔNp73 and its capability to drive hepatocarcinogenesis in vivo [102] . In the case
of ΔNp63, in addition to the mechanisms already described, its oncogenic potential in squamous cell
carcinomas is related to its ability to control transcription of genes involved in skin developmental and
tumorigenic pathways, such as IRF6, IKKa, and FGFR2 [103-105] , and to act as a regulator of p53 tumor
suppressive functions both in a cell-autonomous way and as a mediator of activation of FGF signaling
[26]
pathway in a paracrine way .

THE ROLE OF P53 FAMILY IN THE EMERGENCE, MAINTENANCE AND IMMATURE
PHENOTYPE OF CSCS
Since their discovery, p63 and p73 have been associated with tissue development, because of the multiple
developmental abnormalities observed in tp63 and tp73 knock-out mice . tp63 knock-out mice are
[26]
devoid of stratified and glandular epithelia and die few hours after birth, whereas tp73 knock-out mice
exhibit defects in central nervous system neurogenesis and fertility, but do not develop tumors [18,106-109] .
On the other hand, tp53 knock-out mice exhibit only few developmental abnormalities, but are prone to
the spontaneous development of a variety of neoplasms, mainly lymphomas and sarcomas by 6 months of
age [110,111] . Therefore, due to this prevailing tumor suppressor function, p53 has been extensively studied
in the context of cancer. The role of TAp73 and TAp63 in DNA damage response (DDR) and cancer cell
chemosensitivity [21,96] was also described, whereas their contribution to tumor suppression was established
only later through the analysis of p73 and p63 heterozygous mutation in mice [112] and the generation of
mice selectively lacking TAp73 or TA63 isoforms [113,114] . Fifteen years ago, several groups reported p53 ability
to induce the differentiation of embryonic stem (ES) cells and to negatively regulate the proliferation and
survival of adult neural stem cells [115,116] . Consequently, adult bone marrow of tp53 knock-out mice harbors
less quiescent- and more proliferative- hematopoietic stem cells [117] . More recently, p53 has been shown to
control genomic integrity during reprogramming and to dramatically reduce reprogramming efficiency
in several cell types [118,119] . p53 is also essential for the maintenance of DNA methylation homeostasis in
ES cells [120] . Based on these properties, p53 - known as the “guardian of the genome” since 1992 [121] - has
also been named “guardian of reprogramming” [122] . Notably, some p53 mutants, such as p53R175H and
p53R273H, enhance reprogramming to a level that is higher than that observed in the case of p53 loss, thus
supporting an additional GOF for these mutants [119,123] .

The association of TP53 mutations with poorly differentiated human tumors has been widely reported.
In breast and lung cancers, the presence of p53 mutants has been linked to stem cells and iPSCs (induced
pluripotent stem cells) transcriptional signatures and downregulation of differentiation genes regulated