8626

TP63

tumor protein p63;TP63;tumor protein p63

CUSP|amplified in squamous cell carcinoma|chronic ulcerative stomatitis protein|keratinocyte transcription factor KET|transformation-related protein 63|tumor protein 63|tumor protein p53-competing protein|tumor protein p63 deltaN isoform delta

3q28

protein-coding

Adamantinoma is a rare primary bone neoplasm with epithelial differentiation that is frequently associated with a concomitant fibrous component. Clinical, cytogenetic and histomorphologic overlap has previously been described with osteofibrous dysplasia, thereby suggesting a relationship between these two lesions. We performed a retrospective review of our archives to characterize the clinical and pathologic aspects of adamantinoma and osteofibrous dysplasia diagnosed at our institution, and to compare the expression patterns of p63 and keratin. Nine cases of adamantinoma (six classical, three osteofibrous dysplasia-like) and 11 cases of osteofibrous dysplasia were identified. The epithelial component in adamantinoma was found to stain for p63. Rare cells expressing p63 were also identified in eight cases of osteofibrous dysplasia. expression of p63 was not identified in any of the five cases of fibrous dysplasia controls. The presence of staining for p63, albeit rare, in osteofibrous dysplasia supports the notion of a possible relationship between osteofibrous dysplasia and adamantinoma. Furthermore, our results suggest that, in some situations, p63 may be useful in helping differentiate metastatic carcinoma from adamantinoma.

Some researchs have demonstrated that the loss of delta Np63 is associated with aggressive phenotypes and poor prognosis. However, other research indicates that delta Np63 is considered to have oncogenic properties. Delta Np63 overexpression is often observed in association with the oncogenic growth of squamous cell carcinomas and bladder cancer. In this study, we investigated the oncogenic role of delta Np63 in regulating cell adhesion in transitional cell carcinoma of the bladder (TCCB). The cells were stably transfected with the delta Np63 short hairpin RNA (shRNA) plasmid. Immunocytochemistry was performed to determine the knockdown efficiency. tumour cells were studied for their ability to adhere to vascular endothelial cells. Confocal microscopy was used to analyse the changes in cytoskeletal F-actin. F-actin expression was measured by flow cytometry. Cell invasion ability was assessed using transwell chambers. The delta Np63-silenced tumour cells were shown to adhere more tightly than controls to vascular endothelial cells (P<0.05). The content of F-actin in the delta Np63-silenced cells was enhanced (P<0.05). The Matrigel invasion assays showed that human 5637 bladder cancer cells had a lower degree of motility when transfected with pdelta Np63-shRNA (P<0.05). In conclusion, silencing of the delta Np63 expression can enhance the adhesiveness of 5637 cells by inducing F-actin cytoskeleton production, and it will possibly inhibit the TCCB invasion and metastasis.

BACKGROUND: TAp63 is a tumour-suppressor protein that is often underexpressed in various types of cancer. It has been shown to activate gene transcription depending on the transcription domain and to be closely related with metastasis. In this study, we demonstrate that TAp63 suppresses metastasis in colon cancer cells through microRNA-133b. METHODS: We evaluated the correlation of TAp63 and miR-133b with HT-29 and SW-620 cells and investigated the roles of TAp63 in the expression of RhoA, E-cadherin and vimentin. We further investigated the roles of TAp63-mediated invasion and migration of colon cancer cells. RESULTS: TAp63 expression is downregulated in colon cancer, and microRNA-133b is a transcriptional target of TAp63. Furthermore, microRNA-133b is essential for the inhibitory effects of TAp63 on RhoA, E-cadherin and vimentin. Moreover, TAp63 inhibits cell migration and invasion through microRNA-133b. Correspondingly, the inhibitory effect of TAp63 on RhoA, E-cadherin, vimentin, migration and invasion can be blocked by the microRNA-133b inhibitor. CONCLUSIONS: TAp63 and microRNA-133b were able to suppress the metastasis of colon cancer. Both TAp63 and microRNA-133b may be potential biomarkers for diagnosis in colon cancer metastasis and may provide unique therapeutic targets for this common malignancy.

p63 is an oncogene belonging to the p53 gene family. In normal human skin, p63 is expressed by the least-differentiated keratinocytes of the epidermis and its appendages, by myoepithelial cells of sweat glands, and by a wide variety of primary tumors arising therefrom. The expression of p63 by metastatic skin tumors has been more controversial. In this study, we assessed the usefulness of p63 detection in the differential diagnosis between primary and secondary (metastatic) skin tumors. The expression of p63 was studied in 45 cases of cutaneous metastases, mostly of known primary origin, and 94 benign and malignant epithelial primary skin tumors. p63 was expressed by 85 (89%) of 96 primary skin tumors and 5 (11%) of 45 cutaneous metastases. These results suggest that p63 may be a useful adjunct in the diagnosis of skin carcinomas; however, contrary to what has been previously claimed, expression of p63 does not rule out the metastatic origin of a cutaneous carcinoma.

BACKGROUND: Myoepithelial carcinoma is a rare tumour. The clinical and biological behaviours of these tumours are variable. Although many factors have been evaluated as potential prognostic indicators, including clinical stage, site and size of the tumour, high proliferative activity, extensive invasion into the surrounding tissue, perineural permeation, the abnormal presence of nuclear DNA content, and marked cellular pleomorphism, there are no definite histological features that clearly correlate with their behaviour. Thus, conclusions regarding prognostic factors and ideal treatment may emerge as the number of investigated myoepithelial carcinoma cases accumulate. METHODS: Using immunohistochemistry, expression levels of p63 and Ki-67 were determined in 16 myoepithelial carcinoma samples and correlated with clinicopathological characteristics and patient prognosis. RESULTS: p63 expression was detected in six of the myoepithelial carcinoma tissues (37.5%) and Ki-67 was detected in five (31.3%). In addition, p63 and Ki-67 expression levels were associated with myoepithelial carcinoma recurrence and metastasis. All six patients with p63-positive expression died due to disease or cardiovascular disease (mean survival time = 50.5 months), and p63 expression was statistically significant with respect to survival (P = 0.01). Four patients with Ki-67-positive expression died due to disease or cardiovascular disease (mean survival time = 44.0 months); however, there was no statistically significant difference between Ki-67 expression and survival (P = 0.24). CONCLUSIONS: Recurrence and metastasis in myoepithelial carcinomas are more frequent in p63-positive and Ki-67-positive EMCs, and poor prognosis is associated with overexpression of p63.

INTRODUCTION: Yes-associated protein (YAP) is considered an oncogene found amplified in multiple tumors, including head and neck squamous cell carcinoma (HNSCC). However, the role for YAP expression in HNSCC is not understood. Based on the central role of YAP in the hippo pathway, we tested if YAP was associated with the stage of HNSCC progression and metastatic potential. METHODS: To determine the expression of YAP in human benign and HNSCC tissue specimens, immunohistochemical analyses were performed in whole tissue samples and tissue microarrays. The expression of YAP in tissues of microarray was first associated with clinic-pathologic factors and results verified in samples from whole tissue sections. To investigate the role of YAP and p63 in regulating HNSCC epithelial to mesenchymal transition, epithelial and mesenchymal markers were assayed in Fadu and SCC-25 cells, HNSCC cells with endogenously elevated YAP expression and siRNA-mediated expression knockdown. RESULTS: Analysis of human HNSCC tissues suggested YAP expression was elevated in tumors compared to benign tissues and specifically localized at the tumor invasive front (p value < 0.05). But, indexed YAP expression was lower with greater tumor grade (p value = 0.02). In contrast, p63 expression was primarily elevated in high-grade tumors. Interestingly, both YAP and p63 was strongly expressed at the tumor invasive front and in metastatic HNSCC. Strikingly, we demonstrated YAP expression in the primary HNSCC tumor was associated with nodal metastasis in univariate analysis (p value = 0.02). However, the knockdown of YAP in Fadu and SCC-25 cell lines was not associated with changes in epithelial to mesenchymal transdifferentiation or p63 expression. CONCLUSION: Together, YAP expression, in combination with p63 can facilitate identification of HNSCC tumors from hyperplastic and benign tissues and the metastatic function of YAP in HNSCC may not be a result of epithelia to mesenchymal transdifferentiation.

OBJECTIVE: To study the expression and clinical significance of p63 gene in laryngeal squamous cell carcinoma(LSCC). METHOD: The immunohistochemical technique was used to detected the expression of p63 in 63 cases of LSCC, 45 cases of para-cancer tissues, 24 cases of lymph node metastasis, 40 cases of non lymph node metastasis and 25 normal tissues. RESULT: The positive overexpression rate of the p63 gene in LSCC (95.24%) and in matched metastatic lymph node (83.3%) was significantly higher than para cancer tissues, non metastasis lymph node and normal tissues (P<0.01). p63 gene expression was not correlation with the clinical stages,clinical typing and pathological classification of the LSCC(P >0.05). CONCLUSION: p63 gene had important clinic significance to the diagnosis and differential diagnosis of the LSCC. It perhaps participate in regulation of tumorigenesis in LSCC, and it may play negative feedback action in the development of LSCC.

p63, a recently identified homologue of the p53 gene, has been reported to be essential in the development of epithelia and is mainly expressed by basal and myoepithelial cells. The purpose of this study was to investigate the pattern of p63 expression in cutaneous adnexal neoplasms and to assess its possible value in the differential diagnosis of primary cutaneous neoplasms vs adenocarcinomas metastatic to the skin. Immunohistochemical analysis for p63 was performed on formalin-fixed, paraffin-embedded archival tissue from 20 benign adnexal tumors, 10 malignant adnexal tumors and 14 adenocarcinomas metastatic to the skin. The expression of p63 was evaluated in epidermal cells, skin appendages and metastatic tumor cells. p63 was consistently expressed in the basal and suprabasal cells of epidermis and cutaneous appendages, including the basal/myoepithelial cells of sweat glands. Out of 20 benign adnexal tumors, 13 (65%) showed strong (score 3) p63 expression; the remaining seven (35%) cases had score 2. All primary cutaneous carcinomas, including adenocarcinomas, expressed p63. In contrast, none of the metastatic adenocarcinomas to the skin was positive for p63 (P<0.001). Based on our findings, analysis of p63 expression may help in the differential diagnosis of primary vs metastatic cutaneous adenocarcinomas.

Adenosquamous carcinoma, a rare tumor of the skin with few reported cases in the literature, has not been studied with p63, cytokeratin 5/6 and cytokeratin 7. We stained nine such tumors with these markers. Histologically, the tumors showed superficial, atypical islands of keratinocytes in close association with islands displaying glandular differentiation. Clinically, lesions favored the head and trunk, and a subset of cases showed aggressive behavior. All tumors marked with p63 and cytokeratin 5/6, substantiating that diffuse positivity with these stains is supportive of a primary cutaneous origin. Six tumors stained focally in luminal areas with cytokeratin 7. Recognition of adenosquamous carcinoma is important for appropriate therapy, and stains for p63 and cytokeratin 5/6 may be helpful in ruling out metastatic adenocarcinoma.

TGFbeta ligands act as tumor suppressors in early stage tumors but are paradoxically diverted into potent prometastatic factors in advanced cancers. The molecular nature of this switch remains enigmatic. Here, we show that TGFbeta-dependent cell migration, invasion and metastasis are empowered by mutant-p53 and opposed by p63. Mechanistically, TGFbeta acts in concert with oncogenic Ras and mutant-p53 to induce the assembly of a mutant-p53/p63 protein complex in which Smads serve as essential platforms. Within this ternary complex, p63 functions are antagonized. Downstream of p63, we identified two candidate metastasis suppressor genes associated with metastasis risk in a large cohort of breast cancer patients. Thus, two common oncogenic lesions, mutant-p53 and Ras, selected in early neoplasms to promote growth and survival, also prefigure a cellular set-up with particular metastasis proclivity by TGFbeta-dependent inhibition of p63 function.

Reduced expression of the p53 family member p63 has been suggested to play a causative role in cancer metastasis. Here, we show that DeltaNp63alpha, the predominant p63 isoform, plays a major role in regulation of cell migration, invasion and cancer metastasis. We identified mitogen-activated protein (MAP) kinase phosphatase 3 (MKP3) as a downstream target of DeltaNp63alpha that is required for mediating these effects. We show that DeltaNp63alpha regulates extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) activity via MKP3 in both cancer and non-transformed cells. We further show that exogenous DeltaNp63alpha inhibits cell invasion and is dependent on MKP3 upregulation for repression. Conversely, endogenous pan-p63 ablation results in increased cell migration and invasion, which can be reverted by reintroducing the DeltaNp63alpha isoform alone, but not by other isoforms. Interestingly, these effects require Erk2, but not Erk1 expression, and can be rescued by enforced MKP3 expression. Moreover, MKP3 expression is reduced in invasive cancers, and reduced p63 expression increases metastatic frequency in vivo. Taken together, these results suggest an important role for DeltaNp63alpha in preventing cancer metastasis by inhibition of Erk2 signaling via MKP3.

The control and processing of microRNAs (miRs) is critical in the regulation of all cellular responses. Previous studies have suggested that a reduction in the expression of certain miRs, or an overall decrease in miR processing through the partial depletion of Dicer, can promote enhanced metastatic potential. We show here that Dicer depletion can promote the invasive behavior of cells that is reflected in enhanced recycling and activation of the growth factor receptors Met and EGF receptor. These responses are also seen in response to the expression of tumor-derived mutant p53s, and we show that mutant p53 can down-regulate Dicer expression through both direct inhibition of the TAp63-mediated transcriptional activation of Dicer and a TAp63-independent control of Dicer protein expression. Our results delineate a clear relationship between mutant p53, TAp63, and Dicer that might contribute to the metastatic function of mutant p53 but, interestingly, also reveal TAp63-independent functions of mutant p53 in controlling Dicer activity.

p63 inhibits metastasis. Here, we show that p63 (both TAp63 and DeltaNp63 isoforms) regulates expression of miR-205 in prostate cancer (PCa) cells, and miR-205 is essential for the inhibitory effects of p63 on markers of epithelial-mesenchymal transition (EMT), such as ZEB1 and vimentin. Correspondingly, the inhibitory effect of p63 on EMT markers and cell migration is reverted by anti-miR-205. p53 mutants inhibit expression of both p63 and miR-205, and the cell migration, in a cell line expressing endogenous mutated p53, can be abrogated by pre-miR-205 or silencing of mutated p53. In accordance with this in vitro data, DeltaNp63 or miR-205 significantly inhibits the incidence of lung metastasis in vivo in a mouse tail vein model. Similarly, one or both components of the p63/miR-205 axis were absent in metastases or colonized lymph nodes in a set of 218 human prostate cancer samples. This was confirmed in an independent clinical data set of 281 patients. Loss of this axis was associated with higher Gleason scores, an increased likelihood of metastatic and infiltration events, and worse prognosis. These data suggest that p63/miR-205 may be a useful clinical predictor of metastatic behavior in prostate cancer.