p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis

Matin, Rubeta; Chikh, Anissa; Chong, S.L.; Mesher, David; Graf, Manuela; Sanza, Paolo; Senatore, Valentina; Scatolini, Maria; Moretti, Francesca; Leigh, Irene M.; Proby, Charlotte M.; Costanzo, Antonio; Chiorino, Giovanna; Cerio, R.; Harwood, Catherine A.; Bergamaschi, Daniele

doi:10.1084/jem.20121439

Cited by 59 publications

(49 citation statements)

References 120 publications

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“…TP63 missense mutations of uncertain significance have been found only in a small minority of SCCs (specifically HNSCCs), while they are a frequent occurrence in melanomas, consistent with a proposed role of TP63 in malignant progression of this tumor type (Matin et al, 2013). A direct p63 target of likely relevance in the context of SCC development is FGFR2 , with increased FGFR signaling promoting cancer development (Ferone et al, 2012; Ramsey et al, 2013).…”

Section: Genes Involved In Squamous Cell Fate Determinationsupporting

confidence: 65%

Squamous Cell Cancers: A Unified Perspective on Biology and Genetics

2016

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SUMMARY Squamous cell carcinomas (SCCs) represent the most frequent human solid tumors and a major cause of cancer mortality. These highly heterogeneous tumors arise from closely interconnected epithelial cell populations with intrinsic self-renewal potential inversely related to the stratified differentiation program. SCCs can also originate from simple or pseudo-stratified epithelia through activation of quiescent cells and/or a switch in cell fate determination. Here, we focus on specific determinants implicated in the development of SCCs by recent large-scale genomic, genetic and epigenetic studies and complementary functional analysis. This evidence indicates that SCCs from various body sites, while clinically treated as separate entities, have common determinants, pointing to a unified perspective of the disease and potential new avenues for prevention and treatment.

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Section: Genes Involved In Squamous Cell Fate Determinationsupporting

confidence: 65%

Squamous Cell Cancers: A Unified Perspective on Biology and Genetics

2016

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“…P63 is expressed at high levels in melanoma cell lines and clinical samples and prevents translocation of p53 to the nucleus [121]. This study further expands the role of the aberrations of the p53 pathway in melanomagenesis.…”

Section: Introductionmentioning

confidence: 64%

“…Indeed, several alterations in genes affecting p53 activity have been discovered in melanoma. Among them are the long known mutations in p14ARF[118], overexpression of MDM2 [119], amplification of MDM4 in melanoma[120], elevated expression and the anti-apoptotic role of p53-related protein p63 [121], and increased expression of iASPP [122] -all of which act to inhibit the function of p53. This means that the rare “p53 mutant subtype” could now be expanded to a “p53 pathway aberrations” subtype.…”

Section: Introductionmentioning

confidence: 99%

Pathways and therapeutic targets in melanoma

et al. 2014

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This review aims to summarize the current knowledge of molecular pathways and their clinical relevance in melanoma. Metastatic melanoma was a grim diagnosis, but in recent years tremendous advances have been made in treatments. Chemotherapy provided little benefit in these patients, but development of targeted and new immune approaches made radical changes in prognosis. This would not have happened without remarkable advances in understanding the biology of disease and tremendous progress in the genomic (and other “omics”) scale analyses of tumors. The big problems facing the field are no longer focused exclusively on the development of new treatment modalities, though this is a very busy area of clinical research. The focus shifted now to understanding and overcoming resistance to targeted therapies, and understanding the underlying causes of the heterogeneous responses to immune therapy.

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“…Due to the very few number of clinical data available [6 (33%) out of 18 patients], the prognostic value of cervical SCC samples was not analyzed. The follow-up data of the head and neck SCC patients for up to 138 months were used to evaluate the impact of ΔNp63 expression on overall survival.…”

Section: Resultsmentioning

confidence: 99%

“…Previous data from our laboratory and others showed variable degrees of nuclear p63 expression in SCC tissues [29, 30]. Furthermore, marked overexpression of ΔNp63 has been recently associated with increased proliferation, radiation resistance and unfavorable outcome in the context of several cancers [9, 31-33]. Although ΔNp63 may reduce apoptosis and promote cell proliferation, the implication of ΔNp63 isoforms in soluble factor expression and cancer microenvironment has not been extensively explored.…”

Section: Discussionmentioning

confidence: 99%

ΔNp63 isoform-mediated β-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma

et al. 2014

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Beside a role in normal development/differentiation, high p63 immunoreactivity is also frequently observed in squamous cell carcinoma (SCC). Due to the complexity of the gene, the role of each p63 isotype in tumorigenesis is still confusing. Constitutively produced or induced in inflammatory conditions, human beta-defensins (HβDs) are cationic peptides involved in host defenses against bacteria, viruses and fungi. Here, we investigated both the role of p63 proteins in the regulation of HβDs and the implication of these antimicrobial peptides in tumor (lymph)angiogenesis. Thus, in contrast to TAp63 isotypes, we observed that ΔNp63 proteins (α, β, γ) induce HβD1, 2 and 4 expression. Similar results were observed in cancer tissues and cell lines. We next demonstrated that ΔNp63-overexpressing SCC are associated with both a poor prognosis and a high tumor vascularisation and lymphangiogenesis. Moreover, we showed that HβDs exert a chemotactic activity for (lymphatic) endothelial cells in a CCR6-dependent manner. The ability of HβDs to enhance (lymph)angiogenesis in vivo was also evaluated. We observed that HβDs increase the vessel number and induce a significant increase in relative vascular area compared to negative control. Taken together, the results of this study suggest that ΔNp63-regulated HβD could promote tumor (lymph)angiogenesis in SCC microenvironment.

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p63 is an alternative p53 repressor in melanoma that confers chemoresistance and a poor prognosis

Abstract: p63 is up-regulated in melanoma and prevents nuclear accumulation of p53.

Cited by 59 publications

References 120 publications

Squamous Cell Cancers: A Unified Perspective on Biology and Genetics

Squamous Cell Cancers: A Unified Perspective on Biology and Genetics

Pathways and therapeutic targets in melanoma

ΔNp63 isoform-mediated β-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma

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