The p63 Protein Isoform ΔNp63α Inhibits Epithelial-Mesenchymal Transition in Human Bladder Cancer Cells

Tran, Mai; Choi, Woonyoung; Wszolek, Matthew F.; Navai, Neema; Lee, I-Ling C.; Nitti, Giovanni; Wen, Sijin; Flores, Elsa R.; Siefker-Radtke, Arlene; Czerniak, Bogdan; Dinney, Colin P.; Barton, Michelle C.; McConkey, David J.

doi:10.1074/jbc.m112.408104

Cited by 123 publications

(134 citation statements)

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“…7F). This notion is consistent with a recent study showing that RAS and PIK3CA oncogenes induce epithelial-mesenchymal transition through down-regulation of ΔNp63α (67) and with several studies implicating a role of ΔNp63α in epithelial-mesenchymal transition and cancer metastasis (68)(69)(70). Given that p53 functions as an integrator for cellular stress, including DNA damage, hypoxia, nutrient deprivation, and oxidative stress (71), it is plausible that p53 and p63 are safe guardians against stress signals that impact cell transformation and cancer metastasis.…”

Section: Discussionsupporting

confidence: 79%

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Liang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Activation of phosphatidylinositol 3 kinase (PI3K), Ras, and Her2 signaling plays a critical role in cancer development. Hotspot constitutive activating mutations in oncogenes, such as PIK3CA encoding the p110α catalytic subunit or RAS, as well as overexpression of Her2, are frequently found in human tumors and cancers. It has been well established that activation of these oncogenes profoundly promotes tumor metastasis, whereas decreased expression of ΔNp63α, the major protein isoform of the p53-related p63 expressed in epithelial cells, has been associated with cancer metastasis. In this study, we demonstrate that hotspot oncogenic mutations on PIK3CA and RAS, including p110α H1047R , K-Ras G12V , and H-Ras G12V , as well as activation of Her2, all led to suppression of ΔNp63α expression via Akt-fork-head transcription factor 3a (Akt-FOXO3a) signaling, resulting in increased cell motility and tumor metastasis. Expression of ΔNp63α effectively reversed p110α H1047R -, K-Ras G12V -, H-Ras G12V -, or Her2-induced cell motility in vitro and tumor metastasis in mouse models. We show that ΔNp63α was a direct FOXO3a transcriptional target and that expression of FOXO3a and ΔNp63α was correlated in human cancer biopsy samples. Together, these results demonstrate that ΔNp63α is a common inhibitory target of oncogenic PI3K, Ras, and Her2, and that ΔNp63α may function as a critical integrator of oncogenic signaling in cancer metastasis.PIK3CA | Ras | Her2 | ΔNp63α | cancer metastasis

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Section: Discussionsupporting

confidence: 79%

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Liang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…TP63 (which encodes p63) is expressed in the basal and intermediate cell layers of the normal urothelium. Studies of TP63 isoforms show that Np63 expression is linked to EMT in tumours 169 and this is associated with a more 'basal' phenotype with adverse prognosis [169][170][171] . Recent expression profiling of large numbers of MIBC defines a claudin-low basal subtype (discussed below) that is characterised by the enrichment of EMT markers and the expression of low levels of cytokeratins 37,172 .…”

Section: Emt and Metastasismentioning

confidence: 99%

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

2014

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Correspondence to M.A.K. m.a.knowles@leeds.ac.uk 2 Preface Urothelial carcinoma of the bladder comprises two long-recognised disease entities with distinct molecular features and clinical outcome. Low-grade, non-muscle-invasive tumours recur frequently but rarely progress to muscle invasion, whereas muscle invasive tumours are usually diagnosed de novo and frequently metastasize. Recent genome-wide expression and sequencing studies identify genes and pathways that are key drivers of urothelial cancer and reveal a more complex picture with multiple molecular subclasses that cut across conventional grade and stage groupings. This improved understanding of molecular features, disease pathogenesis and heterogeneity provides new opportunities for prognostic application, disease monitoring and personalised therapy.Bladder cancer is the most common cancer of the urinary tract with approximately 380,000 new cases and 150,000 deaths per year worldwide 1 . It ranks fifth among cancers in men in Western countries.Epidemiological studies identify a range of environmental risk factors, many of which reflect exposure to excreted carcinogenic molecules (BOX 1). Recent genome-wide association studies have also identified germline variants that contribute to risk 2 .In Europe and North America, more than 90% of bladder cancers are urothelial carcinoma. These tumours are staged using the Tumour Nodes Metastasis (TNM) system 3 , which describes the extent of invasion (Tis-T4), and graded according to their cellular characteristics. Two classification systems are in current use 4, 5 .At diagnosis the majority of bladder cancers (~ 60%) are non-muscle-invasive (NMIBC) (stage Ta) NMIBCs frequently recur (50-70%) but infrequently progress to invasion (10-15%) 6 and five-year survival is ~90%. These patients are monitored by cystoscopy and may have multiple resections over many years.Improved monitoring is needed, ideally via urine analysis, which could reduce the morbidity and costs associated with cystoscopy. Although risk tables provide a prognostic tool 7 , no molecular biomarkers accurately predict disease progression. For these patients, localised therapies to remove residual neoplastic and preneoplastic cells post-resection may have major impacts on both quality of life and in health economic terms. MIBCs (>stage T2) have less favourable prognosis with five-year survival <50% and common progression to metastasis (BOX1). Treatment has not advanced for several decades and new approaches to systemic therapy are needed 8 .Improved treatment requires detailed understanding of urothelial carcinoma pathogenesis and molecular biology. A model has evolved, taking into account both histopathological and molecular features. This socalled 'two-pathway' model proposes that papillary NMIBC develops via epithelial hyperplasia and recruitment of a branching vasculature. MIBCs are proposed to develop via flat dysplasia and carcinoma in situ (CIS). The molecular characteristics of MIBC and NMIBC are highly distinct (Tables 1 and 2). Whilst 3 m...

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“…EMT is an important step to enable metastasis and invasiveness. DNp63 is able to activate miR-205, inhibiting the EMT in bladder tumor (Tran et al, 2013). While TAp63 promotes transcription of integrin-recycling genes (D'Aguanno et al, 2014).…”

Section: P63 and Cancermentioning

confidence: 99%

P63 in health and cancer

Gonfloni

Caputo²,

Iannizzotto³

2015

Int. J. Dev. Biol.

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TP63 is the most ancient member of the p53 gene family. The p53 family comprises three transcription factors (p53/p63/p73). They share a high degree of homology and similar domain structure. Yet, they can exist as truncated isoforms. Alternative promoters and splicing sites lead to the generation of several molecules. P53/p63/p73 are important to maintain cell homeostasis. P63 and p73 regulate many p53 target genes. This is due to their common structural features. Both proteins may compensate the loss of p53. This is a common event occurring in more than 50% of malignancies. Yet, p63 (or p73) has its own role. Studies from p63-null mice have shown the key role of p63 in embryo development. Several reports have supported the p63 role in epidermal development and in skin homeostasis. P63 involvement in heart development is currently being researched. Recent studies have found p63 to be "the guardian of human reproduction". In addition, p63 has an important, even controversial, role in cancer. Here, we provide a general overview of p63 regulation and activity. We discuss emerging concepts about its role in germ line protection, metabolism and cancer.

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The p63 Protein Isoform ΔNp63α Inhibits Epithelial-Mesenchymal Transition in Human Bladder Cancer Cells

Cited by 123 publications

References 56 publications

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

P63 in health and cancer

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