Protective role of p53 in skin cancer: Carcinogenesis studies in mice lacking epidermal p53

Page, Angustias; Navarro, Manuel; Suárez-Cabrera, Cristian; Alameda, Josefa P.; Casanova, Mercedes; Paramio, Jesús M.; Bravo, Ana; Ramı́rez, Ángel

doi:10.18632/oncotarget.7897

Cited by 20 publications

(16 citation statements)

References 44 publications

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“…showed that p53 deficiency in mouse embryonic stem cells leads to deregulated DNA methylation patterns, increases phenotypical heterogeneity of these cells and interferes with their differentiation [ 106 ]. Early functional loss of epidermal p53 may also account for the histological diversity of the tumor types in our system, as recently shown in a knock-out mouse model [ 107 ]. Therefore, loss of functional p53 in a nKSCC harboring p53 mutant R266C ( Fig 11 ) may favor dedifferentiation [ 64 ] which could explain the differences in viral load between KSCCs and nKSCCs.…”

Section: Discussionmentioning

confidence: 60%

The interplay of UV and cutaneous papillomavirus infection in skin cancer development

et al. 2017

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Cutaneous human papillomaviruses (HPVs) are considered as cofactors for non-melanoma skin cancer (NMSC) development, especially in association with UVB. Extensively studied transgenic mouse models failed to mimic all aspects of virus-host interactions starting from primary infection to the appearance of a tumor. Using the natural model Mastomys coucha, which reflects the human situation in many aspects, we provide the first evidence that only UVB and Mastomys natalensis papillomavirus (MnPV) infection strongly promote NMSC formation. Using UVB exposures that correspond to UV indices of different geographical regions, irradiated animals developed either well-differentiated keratinizing squamous cell carcinomas (SCCs), still supporting productive infections with high viral loads and transcriptional activity, or poorly differentiated non-keratinizing SCCs almost lacking MnPV DNA and in turn, early and late viral transcription. Intriguingly, animals with the latter phenotype, however, still showed strong seropositivity, clearly verifying a preceding MnPV infection. Of note, the mere presence of MnPV could induce γH2AX foci, indicating that viral infection without prior UVB exposure can already perturb genome stability of the host cell. Moreover, as shown both under in vitro and in vivo conditions, MnPV E6/E7 expression also attenuates the excision repair of cyclobutane pyrimidine dimers upon UVB irradiation, suggesting a viral impact on the DNA damage response. While mutations of Ras family members (e.g. Hras, Kras, and Nras) were absent, the majority of SCCs harbored—like in humans—Trp53 mutations especially at two hot-spots in the DNA-binding domain, resulting in a loss of function that favored tumor dedifferentiation, counter-selective for viral maintenance. Such a constellation provides a reasonable explanation for making continuous viral presence dispensable during skin carcinogenesis as observed in patients with NMSC.

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Section: Discussionmentioning

confidence: 60%

The interplay of UV and cutaneous papillomavirus infection in skin cancer development

et al. 2017

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“…The genotyping of K5-IKKβ, p53 EKO /K5-IKKβ and Ink4a/Arf KO /K5-IKKβ mice was performed by PCR analysis of tail DNA as previously described. [35][36][37][38] K5-IKKβ mice are available from the European Mouse Mutant Archive (code EM:09179). The expected genotypes were obtained in roughly Mendelian rates in the different crosses.…”

Section: Methodsmentioning

confidence: 99%

IKKβ overexpression together with a lack of tumour suppressor genes causes ameloblastic odontomas in mice

et al. 2020

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Odontogenic tumours are a heterogeneous group of lesions that develop in the oral cavity region and are characterized by the formation of tumoural structures that differentiate as teeth. Due to the diversity of their histopathological characteristics and clinical behaviour, the classification of these tumours is still under debate. Alterations in morphogenesis pathways such as the Hedgehog, MAPK and WNT/β-catenin pathways are implicated in the formation of odontogenic lesions, but the molecular bases of many of these lesions are still unknown. In this study, we used genetically modified mice to study the role of IKKβ (a fundamental regulator of NF-κB activity and many other proteins) in oral epithelial cells and odontogenic tissues. Transgenic mice overexpressing IKKβ in oral epithelial cells show a significant increase in immune cells in both the oral epithelia and oral submucosa. They also show changes in the expression of several proteins and miRNAs that are important for cancer development. Interestingly, we found that overactivity of IKKβ in oral epithelia and odontogenic tissues, in conjunction with the loss of tumour suppressor proteins (p53, or p16 and p19), leads to the appearance of odontogenic tumours that can be classified as ameloblastic odontomas, sometimes accompanied by foci of secondary ameloblastic carcinomas. These tumours show NF-κB activation and increased β-catenin activity. These findings may help to elucidate the molecular determinants of odontogenic tumourigenesis and the role of IKKβ in the homoeostasis and tumoural transformation of oral and odontogenic epithelia.

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“…Mouse experimental procedures were performed according to European and Spanish regulations and were approved by the Ethics Committee for Animal Welfare of CIEMAT and by the legal authority (protocol codes BME02/10 and PROEX086/15). Transgenic mice used in this work have been described previously: line L1of K5-IKKb mice in B6D2 hybrid background (20); TgAC (FVB/ NTac-Tg(Hba-x-v-Ha-ras)TG.ACLed) mice (21), p53 EKO mice (22,23), and Ink4a/Arf KO mice (lacking p16 and p19 proteins in FVB background; ref. 24).…”

Section: Mice and Treatmentsmentioning

confidence: 99%

“…Genotyping of K5-IKKb and of p53 and Ink4a/Arf loci were performed by PCR analysis of tail DNA, as described previously (20,23,25).…”

Section: Genotyping Of Micementioning

confidence: 99%

“…To this end, we crossed K5-IKKb mice with p53 fl/fl /K14-Cre mice (22,33). These mice efficiently delete p53 exons 2 to 10 in the vast majority of epidermal cells (23), and so we named them p53 EKO mice; mice carrying both genetic modifications (i.e., p53 EKO /K5-IKKb mice), simultaneously lack p53 and overexpress IKKb in skin basal proliferative cells, where skin tumors arise. We performed a two-stage skin carcinogenesis experiment and compared the rate of tumor appearance, tumor size, and histologic classification between p53 EKO /K5-IKKb and control p53 EKO mice (Fig.…”

Section: The Skin Tumor-suppressive Activity Of Ikkb Is Independent Omentioning

confidence: 99%

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IKKβ-Mediated Resistance to Skin Cancer Development Is Ink4a/Arf-Dependent

Page

Bravo

Suárez-Cabrera

et al. 2017

Molecular Cancer Research

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IKKβ (encoded by ) is a protein kinase that regulates the activity of numerous proteins important in several signaling pathways, such as the NF-κB pathway. IKKβ exerts a protumorigenic role in several animal models of lung, hepatic, intestinal, and oral cancer. In addition, genomic and proteomic studies of human tumors also indicate that gene is amplified or overexpressed in multiple tumor types. Here, the relevance of IKKβ in skin cancer was determined by performing carcinogenesis studies in animal models overexpressing IKKβ in the basal skin layer. IKKβ overexpression resulted in a striking resistance to skin cancer development and an increased expression of several tumor suppressor proteins, such as p53, p16, and p19. Mechanistically, this skin tumor-protective role of IKKβ is independent of p53, but dependent on the activity of the locus. Interestingly, in the absence of p16 and p19, IKKβ-increased expression favors the appearance of cutaneous spindle cell-like squamous cell carcinomas, which are highly aggressive tumors. These results reveal that IKKβ activity prevents skin tumor development, and shed light on the complex nature of IKKβ effects on cancer progression, as IKKβ can both promote and prevent carcinogenesis depending on the cell type or molecular context. The ability of IKKβ to promote or prevent carcinogenesis suggests the need for further evaluation when targeting this protein. .

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Protective role of p53 in skin cancer: Carcinogenesis studies in mice lacking epidermal p53

Cited by 20 publications

References 44 publications

The interplay of UV and cutaneous papillomavirus infection in skin cancer development

The interplay of UV and cutaneous papillomavirus infection in skin cancer development

IKKβ overexpression together with a lack of tumour suppressor genes causes ameloblastic odontomas in mice

IKKβ-Mediated Resistance to Skin Cancer Development Is Ink4a/Arf-Dependent

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