Overexpression of p63 is associated with radiation resistance and prognosis in oral squamous cell carcinoma

Moergel, Maximilian; Abt, Eva Christine; Stockinger, Marcus; Kunkel, Martin

doi:10.1016/j.oraloncology.2010.06.012

Cited by 38 publications

(40 citation statements)

References 30 publications

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“…Overall survival was significantly higher for patients with low ΔNp63 expression compared with those displaying a high expression for this p63 isoform. In agreement with our results, data reported that the overexpression of p63 in oral SCC was associated with poor radiation response and shorter survival [31, 32]. However, in contrast to our data, these studies did not reveal a potential mechanism and used a pan-antibody targeting all p63 transcripts; thus different p63 isoforms were not analyzed separately.…”

Section: Discussionsupporting

confidence: 89%

“…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%

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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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Section: Discussionsupporting

confidence: 89%

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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“…According to the manufacturer's specification, this antibody was raised against amino acids 1-205 mapping at the N-terminal portion of ΔNp63. Several studies using the monoclonal A4A antibody made by this company showed similar findings to our results, meanwhile previous studies using other antibodies had opposite findings and outcomes (25,49,52). Foschini et al also analyzed the expression of TAp63 in the excised OSCC specimens by reverse transcription-polymerase chain reaction and nested polymerase chain reaction, and found that the patients with TAp63 expression have favorable outcomes (56).…”

Section: Discussionsupporting

confidence: 86%

“…Several studies on the assessment of correlation between the positive rate of p63 and patient prognosis in head and neck carcinoma have been reported (25,49,(52)(53)(54)(55). Lo Muzio et al and Moergel et al also have found that the high expression of p63 is significantly associated with the poor prognosis (49,52).…”

Section: Discussionmentioning

confidence: 99%

Increased ΔNp63 expression is predictive of malignant transformation in oral epithelial dysplasia and poor prognosis in oral squamous cell carcinoma

et al. 2011

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Abstract. This study examined immunohistochemical expression of ΔNp63, a keratinocyte stem cell marker, in oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) and then to elucidate usefulness of ΔNp63 as a marker for diagnosis and prognosis. One-hundred and twelve cases of OL and 81 cases of OSCC were analyzed by immunohistochemical staining for ΔNp63, Ki-67, and cytokeratin 14. These labeling indices (LIs) were calculated, and the association of these LIs with clinicopathologic characteristics in the OL and OSCC was evaluated. In the OL, these LIs increased significantly according to the severity of epithelial dysplasia (p<0.0001). ΔNp63-LI in the OL with malignant transformation was significantly higher than that in the OL without (49.3 vs. 34.2%; p<0.01). In the OSCC, the LIs increased significantly in association with the histologic grade (p<0.0001). A significant difference between the high and low ΔNp63-LI groups was found in the incidence of cervical lymph node and distant metastasis (p<0.05). The prognosis of the high ΔNp63-LI (mean value >73.8%) group is poorer than that of the low ΔNp63-LI (mean value ≤73.8%) group (p<0.05). These results suggested that increased ΔNp63 expression is involved in malignant transformation in epithelial dysplasia and poor prognosis in OSCC. Introductionp63 gene is a homolog of p53, it is located on chromosome 3q27-29 and encodes multiple isotypes with divergent abilities in a variety of organs (1-4). p63 has two different promoter domains that generate two protein isoforms, TAp63 and ΔNp63; each isoform yields three isotypes (α, β, γ) generated by alternative splicing of the p63 COOH terminus; and TAp63 includes an NH 2 -terminal transactivation domain, which is absent in ΔNp63 (1-4,6,7). TAp63 transactivates p53 target genes to induce apoptosis by inhibiting cell proliferation in response to exposure of cells to DNA-damaging agents such as ultraviolet irradiation. In contrast, ΔNp63 exerts dominant-negative activities against TAp63 and p53, and ΔNp63 is thus considered as an oncoprotein (1,(5)(6)(7)(8)(9)(10)(11)(12)(13)(14).Recent studies have shown that p63 is essential for craniofacial development during morphogenesis, because p63 -/-mice represented craniofacial abnormalities including hypoplasia of jaws and defects of the teeth, hair follicles, lachrymal glands, and salivary glands (1,15). Furthermore, p63 -/-mice showed lack of squamous stratification in the epidermis and oral epithelium, suggesting that p63 plays critical roles in the epithelial development. Pellegrini et al also demonstrated that p63 was expressed in keratinocyte stem cells and involved in the proliferation and maintenance of this cell population (16). Thus, p63 has been characterized as a marker of keratinocyte stem cells.In the tumorigenesis as well as morphogenesis, the existence of a stem-like cell population with a self-renewal potential, capacity of development into multiple lineages, extensive proliferation activity, and high migration capability in the tumor tissue was revealed. ...

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“…In the present study, univariate and multivariate analysis revealed the prognostic significance of β-catenin and ΔNp63 in oral squamous cell carcinoma as mentioned by Odajima et al [34] for β-catenin and by Lo Muzio et al [35] and Moergel et al [36] for ΔNp63. This suggests that β-catenin and ΔNp63 may be used as independent prognostic markers of oral squamous cell carcinoma.…”

Section: Discussionsupporting

confidence: 74%

Aberrant expression of β-catenin and its association with ΔNp63, Notch-1, and clinicopathological factors in oral squamous cell carcinoma

Gokulan

Devaraj

2011

Clin Oral Invest

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The present study focuses on the correlation between the expression pattern of β-catenin (component of Wnt signaling), ΔNp63 (proliferation marker), and Notch 1 (transmembrane receptor) in oral squamous cell carcinoma. The study also aims to investigate the interaction between β-catenin and ΔNp63 in oral cancer. Furthermore, we also analyzed the prognostic significance of β-catenin, ΔNp63, and Notch 1 in oral squamous cell carcinoma. Immunohistochemical analysis of β-catenin, ΔNp63, and Notch 1 were done in 62 cases of oral squamous cell carcinoma. Co-immunoprecipitation analysis was done to study the possible interaction between β-catenin and ΔNp63 in oral cancer. Kaplan-Meier method was used to estimate overall and disease-free survival, and the Log-rank test was used to compare the resulting curves. Statistically significant positive correlation was found between the localization of β-catenin and the expression of ΔNp63 (p = 0.001**, r (s) = 0.427), whereas, no significant association was found between the expression pattern of β-catenin and Notch 1. Interestingly, interaction between β-catenin and ΔNp63 was observed in oral carcinoma. Moreover, β-catenin and ΔNp63 may be related to worst survival in oral carcinoma. Statistically significant positive association between localization of β-catenin and expression of ΔNp63 suggests that they might have dependent roles in maintaining the proliferation of oral carcinoma cells. In addition, the downregulated expression of Notch 1 was related to invasion and differentiation status of oral carcinoma cells. Furthermore, β-catenin and ΔNp63 may be used as independent prognostic markers of oral carcinoma. On the other hand, interaction of β-catenin with ΔNp63 may be a key event in maintaining the proliferation of oral carcinoma cells. The present study indicates that β-catenin and ΔNp63 may be used as independent prognostic markers of oral carcinoma and the interaction of β-catenin with ΔNp63 may be a crucial event in regulating proliferation and differentiation of oral carcinoma cells, which may be used as a target for therapeutic implications.

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Overexpression of p63 is associated with radiation resistance and prognosis in oral squamous cell carcinoma

Cited by 38 publications

References 30 publications

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

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

Increased ΔNp63 expression is predictive of malignant transformation in oral epithelial dysplasia and poor prognosis in oral squamous cell carcinoma

Aberrant expression of β-catenin and its association with ΔNp63, Notch-1, and clinicopathological factors in oral squamous cell carcinoma

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