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Expression profiling of cutaneous squamous cell carcinoma with perineural invasion implicates the p53 pathway in the process

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ABSTRACT

Squamous cell carcinoma (SCC) is the second most common cancer worldwide and accounts for approximately 30% of all keratinocyte cancers. The vast majority of cutaneous SCCs of the head and neck (cSCCHN) are readily curable with surgery and/or radiotherapy unless high-risk features are present. Perineural invasion (PNI) is recognized as one of these high-risk features. The molecular changes during clinical PNI in cSCCHN have not been previously investigated. In this study, we assessed the global gene expression differences between cSCCHN with or without incidental or clinical PNI. The results of the analysis showed signatures of gene expression representative of activation of p53 in tumors with PNI compared to tumors without, amongst other alterations. Immunohistochemical staining of p53 showed cSCCHN with clinical PNI to be more likely to exhibit a diffuse over-expression pattern, with no tumors showing normal p53 staining. DNA sequencing of cSCCHN samples with clinical PNI showed no difference in mutation number or position with samples without PNI, however a significant difference was observed in regulators of p53 degradation, stability and activity. Our results therefore suggest that cSCCHN with clinical PNI may be more likely to contain alterations in the p53 pathway, compared to cSCCHN without PNI.

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Differential expression of regulators of p53 degradation, stability and activity in cSCCHN with clinical PNI.Selected target genes known to play roles in degradation, stability and activity of p53 were taken from the expression profiling dataset, and plotted as box and whisker (maximum and minimum) plots. Groups are as indicated, showing normalized gene expression (log2) of each of the tumors included in the analysis. Data was analyzed using one-way ANOVA with multiple comparisons. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
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f4: Differential expression of regulators of p53 degradation, stability and activity in cSCCHN with clinical PNI.Selected target genes known to play roles in degradation, stability and activity of p53 were taken from the expression profiling dataset, and plotted as box and whisker (maximum and minimum) plots. Groups are as indicated, showing normalized gene expression (log2) of each of the tumors included in the analysis. Data was analyzed using one-way ANOVA with multiple comparisons. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Mentions: To further investigate the differences in p53 staining in cSCCHN with clinical PNI in the absence of significant differences in mutational burden or position, we examined the expression of known regulators of p53 degradation and stability. We observed significant increases in expression of MDM2, a molecule known to target p53 for ubiquitination and degradation24, in cSCCHN with either incidental or clinical PNI as well as in expression of MDM4, a related inhibitor of p53 activity25 (Fig. 4). In contrast, another E3 ubiquitin ligase RCHY1 (Pirh2) was significantly down-regulated in cSCCHN with clinical PNI. Most interestingly, the deubiquitinating enzymes encoded by USP2 and USP7 (HAUSP) that target MDM2 were significantly down-regulated in tumors with clinical PNI (Fig. 4). Expression of RASSF1, the product of which disrupts the interaction between MDM2 and HAUSP was significantly up-regulated in the clinical PNI samples. These results suggest the balance of molecules controlling p53 degradation, stability and activity is altered in cSCCHN with clinical PNI.


Expression profiling of cutaneous squamous cell carcinoma with perineural invasion implicates the p53 pathway in the process
Differential expression of regulators of p53 degradation, stability and activity in cSCCHN with clinical PNI.Selected target genes known to play roles in degradation, stability and activity of p53 were taken from the expression profiling dataset, and plotted as box and whisker (maximum and minimum) plots. Groups are as indicated, showing normalized gene expression (log2) of each of the tumors included in the analysis. Data was analyzed using one-way ANOVA with multiple comparisons. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5035993&req=5

f4: Differential expression of regulators of p53 degradation, stability and activity in cSCCHN with clinical PNI.Selected target genes known to play roles in degradation, stability and activity of p53 were taken from the expression profiling dataset, and plotted as box and whisker (maximum and minimum) plots. Groups are as indicated, showing normalized gene expression (log2) of each of the tumors included in the analysis. Data was analyzed using one-way ANOVA with multiple comparisons. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.
Mentions: To further investigate the differences in p53 staining in cSCCHN with clinical PNI in the absence of significant differences in mutational burden or position, we examined the expression of known regulators of p53 degradation and stability. We observed significant increases in expression of MDM2, a molecule known to target p53 for ubiquitination and degradation24, in cSCCHN with either incidental or clinical PNI as well as in expression of MDM4, a related inhibitor of p53 activity25 (Fig. 4). In contrast, another E3 ubiquitin ligase RCHY1 (Pirh2) was significantly down-regulated in cSCCHN with clinical PNI. Most interestingly, the deubiquitinating enzymes encoded by USP2 and USP7 (HAUSP) that target MDM2 were significantly down-regulated in tumors with clinical PNI (Fig. 4). Expression of RASSF1, the product of which disrupts the interaction between MDM2 and HAUSP was significantly up-regulated in the clinical PNI samples. These results suggest the balance of molecules controlling p53 degradation, stability and activity is altered in cSCCHN with clinical PNI.

View Article: PubMed Central - PubMed

ABSTRACT

Squamous cell carcinoma (SCC) is the second most common cancer worldwide and accounts for approximately 30% of all keratinocyte cancers. The vast majority of cutaneous SCCs of the head and neck (cSCCHN) are readily curable with surgery and/or radiotherapy unless high-risk features are present. Perineural invasion (PNI) is recognized as one of these high-risk features. The molecular changes during clinical PNI in cSCCHN have not been previously investigated. In this study, we assessed the global gene expression differences between cSCCHN with or without incidental or clinical PNI. The results of the analysis showed signatures of gene expression representative of activation of p53 in tumors with PNI compared to tumors without, amongst other alterations. Immunohistochemical staining of p53 showed cSCCHN with clinical PNI to be more likely to exhibit a diffuse over-expression pattern, with no tumors showing normal p53 staining. DNA sequencing of cSCCHN samples with clinical PNI showed no difference in mutation number or position with samples without PNI, however a significant difference was observed in regulators of p53 degradation, stability and activity. Our results therefore suggest that cSCCHN with clinical PNI may be more likely to contain alterations in the p53 pathway, compared to cSCCHN without PNI.

No MeSH data available.


Related in: MedlinePlus