It is poorly understood how a single protein, p53, can be responsive to so many stress signals and orchestrates very diverse cell responses to maintain/restore cell/tissue functions. The uncovering that TP53 gene physiologically expresses, in a tissue-dependent manner, several p53 splice variants (isoforms) provides an explanation to its pleiotropic biological activities. Here, we summarize a decade of research on p53 isoforms. The clinical studies and the diverse cellular and animal models of p53 isoforms (zebrafish, Drosophila, and mouse) lead us to realize that a p53-mediated cell response is, in fact, the sum of the intrinsic activities of the coexpressed p53 isoforms and that unbalancing expression of different p53 isoforms leads to cancer, premature aging, (neuro)degenerative diseases, inflammation, embryo malformations, or defects in tissue regeneration. Cracking the p53 isoforms' code is, thus, a necessary step to improve cancer treatment. It also opens new exciting perspectives in tissue regeneration.

Prostate cancer is the second most common cancer in men, for which there are no reliable biomarkers or targeted therapies. Here we demonstrate that elevated levels of Δ133TP53β isoform characterize prostate cancers with immune cell infiltration, particularly T cells and CD163+ macrophages. These cancers are associated with shorter progression-free survival, Gleason scores ≥ 7, and an immunosuppressive environment defined by a higher proportion of PD-1, PD-L1 and colony-stimulating factor 1 receptor (CSF1R) positive cells. Consistent with this, RNA-seq of tumours showed enrichment for pathways associated with immune signalling and cell migration. We further show a role for hypoxia and wild-type p53 in upregulating Δ133TP53 levels. Finally, AUC analysis showed that Δ133TP53β expression level alone predicted aggressive disease with 88% accuracy. Our data identify Δ133TP53β as a highly accurate prognostic factor for aggressive prostate cancer.

As tumor protein 53 (p53) isoforms have tumor‐promoting, migration, and inflammatory properties, this study investigated whether p53 isoforms contributed to glioblastoma progression. The expression levels of full‐length TP53α (TAp53α) and six TP53 isoforms were quantitated by RT‐qPCR in 89 glioblastomas and correlated with TP53 mutation status, tumor‐associated macrophage content, and various immune cell markers. Elevated levels of Δ133p53β mRNA characterised glioblastomas with increased CD163‐positive macrophages and wild‐type TP53. In situ‐based analyses found Δ133p53β expression localised to malignant cells in areas with increased hypoxia, and in cells with the monocyte chemoattractant protein C‐C motif chemokine ligand 2 (CCL2) expressed. Tumors with increased Δ133p53β had increased numbers of cells positive for macrophage colony‐stimulating factor 1 receptor (CSF1R) and programmed death ligand 1 (PDL1). In addition, cells expressing a murine ‘mimic’ of Δ133p53 (Δ122p53) were resistant to temozolomide treatment and oxidative stress. Our findings suggest that elevated Δ133p53β is an alternative pathway to TP53 mutation in glioblastoma that aids tumor progression by promoting an immunosuppressive and chemoresistant environment. Adding Δ133p53β to a TP53 signature along with TP53 mutation status will better predict treatment resistance in glioblastoma. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity through the discovery that TP53 differentially expresses twelve p53 protein isoforms in human cells with both overlapping and unique biologic activities. Here, we summarize the current knowledge on the Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ), which are evolutionary derived and found only in human and higher order primates. All three isoforms lack both of the transactivation domains and the beginning of the DNA-binding domain. Despite the absence of these canonical domains, the Δ133p53 isoforms maintain critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. The ability of the Δ133p53 isoforms to modulate the p53 pathway functions underscores the need to include these p53 isoforms in our understanding of how the p53 pathway contributes to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies.

Despite tremendous efforts from scientists and clinicians worldwide, pancreatic adenocarcinoma (PDAC) remains a deadly disease due to the lack of early diagnostic tools and reliable therapeutic approaches. Consequently, a majority of patients (80%) display an advanced disease that results in a low resection rate leading to an overall median survival of less than 6 months. Accordingly, robust markers for the early diagnosis and prognosis of pancreatic cancer, or markers indicative of survival and/or metastatic disease are desperately needed to help alleviate the dismal prognosis of this cancer. In addition, the discovery of new therapeutic targets is mandatory to design effective treatments. In this review, we will highlight the translational studies demonstrating that microRNAs may soon translate into clinical applications as long-awaited screening tools and therapeutic targets for PDAC.

Introduction Src oncogene have been strongly implicated in the development, growth, progression, and metastasis of a variety of human cancers. Although soy isoflavones have been shown to have potential anticancer activity, the role of isoflavones in the oncogenic activity of Src remains unknown. Using HAG-1 human adenocarcinoma cells transfected with v-src, we investigated the functional role of Src in anti-proliferative activity of isoflavones such as genistein, daidzein, glycitin and equol. Material and methods The growth inhibitory activities of those isoflavones against Src-and vehicle-transfected cells (HAG/src and HAG/neo) were investigated using WST-1 cell proliferation assay. Effects of those isoflavones on apoptosis and cell cycle perturbation were evaluated by FACS analyses.Results and discussions The growth of HAG/neo cells was inhibited potently by genistein and equol, but modestly by daidzein and glycitin. In contrast, activated Src conferred resistance to either daidzein, glycitin or equol, but rendered the cells more sensitive to genistein, compared to HAG/neo; Genistein strongly inhibited the growth of HAG/src cells in a dose-dependent manner with IC50 value of 25 mM, whereas in other three isoflavones, the inhibitory effects were minimal without reaching an IC50 even at a dose of 100 mM. Upon treatment with 50 mM genistein for 72 hour, HAG/src cells were significantly arrested at the G2/M compared to HAG/neo cells (37.7% versus 7.0%). By contrast, the same concentration of either daidzein, glycitin or equol could not arrest HAG/src cells at any checkpoint of the cell cycle. The sub-G0/G1 apoptotic cell populations were not increased following 72 hour exposure with either isoflavones. Therefore, it appears that growth inhibition by genistein in Src-activated cells would be mediated mainly by the G2/M arrest of cell cycle rather than apoptosis induction. Genistein increased the expression levels of p53 and p21 with decreased phosphorylated p21. The levels of other main cell cycle-related proteins such as cyclin B, cyclin E, CDK2, and cdc2 were not altered. These data suggest that genistein would be the only isoflavone component that may potentially suppress oncogenic activity driven by Src through increasing the p53 and p21 levels. Conclusion These data suggest that genistein would be the only isoflavone component that may potentially suppress oncogenic activity driven by Src, providing a mechanistic rationale for the potential use of genistein in the prevention and treatment of human cancers with activated Src.

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