STAT3, STAT5A, STAT5B and STAT6 proteins are overexpressed in human basal cell carcinoma.

BACKGROUND: The molecular pathogenesis of basal cell carcinoma (BCC) is still not precisely described and is the subject of ongoing studies. The role of signal transducers and activators of transcription (STATs) in human epithelial carcinogenesis has been poorly investigated, but in the era of studies on inhibitors targeting STAT proteins this topic seems worth exploring. Increased expression of STAT3 in human nonmelanoma skin cancer (NMSC) has been confirmed in a few studies, but to our knowledge, expression of STAT5A, STAT5B and STAT6 in BCC has not been previously evaluated. AIM: To measure expression of STAT3, STAT5A, STAT5B and STAT6 expression in different histopathological subtypes of human BCC and its correlation with selected clinical variables. METHODS: Immunohistochemistry was used to assess 60 BCC tumour specimens [20 superficial (s)BCCs, 20 nodular (n)BCCs and 20 infiltrative (i)BCCs] and to compare with specimens of healthy skin. There was no significant difference in age or sex between the three groups of patients with BCC. As many tumours showed heterogeneity of staining, the H-score system was applied to calculate the intensity of immunoexpression. RESULTS: Expression of STAT3, STAT5A, STAT5B and STAT6 was observed in all histopathological subtypes of BCC, and was stronger than the expression within the adjacent epidermis and also stronger than the expression within the epidermis in the healthy control group. Statistical analysis revealed no significant differences in mean H-scores calculated for sBCCs, nBCCs and iBCCs. There were no statistically significant associations between STAT3, STAT5A, STAT5B and STAT6 expression and patient sex/age, and tumour size/site. CONCLUSION: Our results confirm a possible role of STATs in the pathogenesis of BCC and should encourage future investigations on the possible therapeutic implications of this finding.

Expression pattern of ISL-1, TTF-1 and PAX5 in olfactory neuroblastoma.

Olfactory neuroblastoma (ONB) is a rare neoplasm of the sinonasal area with neuroendocrine differentiation. ISL-1, TTF-1 and PAX5 are transcription factors that are frequently upregulated in tumors showing neuroendocrine differentiation. The aim of our study was to evaluate these markers in a group of ONBs. We included 11 ONBs from 4 large university hospitals. Immunohistochemical expression of TTF-1, PAX5 and ISL-1 was evaluated. TTF-1, ISL-1 and PAX5 were expressed in 3/11 cases (27.27%, h-score: 3-45), 7/11 cases (63.64%, h-score: 23-200), and in 3/11 cases (27.77%, h-score 3-85), respectively. The patient with the strongest PAX5 reactivity exhibited an aggressive clinical course with rapid dissemination to the spine and death shortly after the diagnosis. No significant correlation in the expression of PAX5 and TTF-1 ( = 0.43; p = 0.18) was observed. ISL-1 is widely expressed in tumors with neuroendocrine differentiation and therefore of limited value in their differential diagnosis. TTF-1 positivity does not exclude the diagnosis of primary ONB, although usually only a small percentage of cells are positive. PAX5 expression is infrequent (27.27%) in ONB; however, if present it can be associated with a very aggressive clinical course.

The relationship between constitutive ATP release and its extracellular metabolism in isolated rat kidney glomeruli.

ATP and adenosine are important extracellular regulators of glomerular functions. In this study, ATP release from glomeruli suspension and its extracellular metabolism were investigated. Basal extraglomerular ATP concentration (1nM) increased several fold during inhibition of ecto-ATPase activity, reflecting the basal ATP release rate. Mechanical perturbation increased the amounts of ATP released from glomeruli. ATP added to glomeruli was almost completely degraded within 20 minutes. In that time, AMP was the main product of extracellular ATP metabolism. Significant accumulation of AMP was observed after 5 min (194 +/-16 microM) and 20 min (271 +/-11 microM), whereas at the same time concentration of adenosine was only 10 muM. A competitive inhibitor of ecto-5-nucleotidase alpha-beta-methylene-ADP (AOPCP), decreased extraglomerular ATP and adenosine concentration by 80% and 50%, respectively. Similarly, AMP (100 microM) also markedly reduced extraglomerular ATP accumulation, whereas IMP, its deamination product, was not effective. P1, P5-diadenosine pentaphosphate (Ap5A) - an inhibitor of ecto-adenylate kinase prevented significantly the disappearance of ATP from extraglomerular media caused by AMP. These findings demonstrate that the decrease in extracellular ATP concentration observed after addition of AOPCP or AMP is caused by the presence of ecto-adenylate kinase activity in the glomeruli. The enzyme catalyses reversible reaction 2ADP<->ATP+AMP, and a rise in the AMP concentration can lead to fall in ATP level. The present study provides evidence the extraglomerular accumulation of ATP reflects both release of ATP from glomeruli cells and its metabolism by ecto-enzymes. Our data suggest that AMP, produced from ATP in the Bowman's capsular space, might plays a dual role as a substrate for ecto-adenylate kinase and ecto-nucleotidase reactions being responsible for the regulation of intracapsular ATP and adenosine concentration. We conclude that AMP degrading and converting ecto-enzymes effectively determine the balance between ATP and adenosine concentration and thus the activation of P2 and/or adenosine receptors.