| IntroductionPituitary tumors account for approximately10% to 25% of intracranial tumors and are common benign intracranial neoplasm. They arise from highly differentiated anterior pituitary cells expressing one or more pituitary hormone gene products. According to pathological classification, pituitary tumors can be divided into different subtypes, such as growth hormone adenoma(GH), prolactin(PRL),adrenocorticotrophic hormone and non-functi-Oning(NF)adenoma. Different subtypes show different clinical symptoms, such as amenorrhoea, menstruation, cushing symptoms or just oppression symptoms. In general, most pituitary adenomas grow slowly, but some of them demonstrate malignant beheviors such as rapid invasive growth, non-response to conventional therapy including surgery, radiotherapy and pharmacological treatment. Evaluation of biological behaviour of pituitary adenoma may provide helpful information for prediction of the patient’s prognosis and for treatment. However, it is difficult to estimate the biological behaviour and subtle morphological differences of diverse tumors using only conventional histopathological methods or clinical features. So further research about molecular mechanism of pituitary adenomas are very valuable to the prevention, diagnosis, prognosis and treatment selection of pituitary adenoma.The Janus protein tyrosine kinase/Signal transducer and activator of transcription signal pathway is one of the main signal pathways for transducing signals from the cell surface to the nucleus. Until now,Seven members of SATA family in mammals have been identified, including STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5a and STAT6. STAT3 is a major member of STATs. STAT3 was latent in cytoplasm and activated through tyrosing phosphorylation. Phosphorylated STAT3 forms homo-or hetero-dimer and translocates to nucleus to promote the transcription of target gene (e. g PTTG、VEGF、MMP2、Cyclin-Dl) and further mediate cell survival, growth, differentiation, angiogenesis. Sustained activation of STAT3 results in abnormally high expression of its target genes, consequently shows carcino-genic effects. Now the tumorigenic mechanism of pituitary adenoma is not clearly understood. However the relationship between STAT3 and its downstream target gene PTTG in pituitary adenoma have not been reported around the world.ObjectiveIn this study we used immunohischemistry, western blot analysis and Real Time PCR methods to detect STAT3, p-STAT3 and PTTG protein and mRNA expression in pituitary adenoma. Furthermore, the above mentioned 3 genes correlation and their clinicopathological significance of pituitary adenoma have been explored. In conclusion, we studied whether PTTG expression regulated by STAT3 signal pathway might be involved in the pathogenesis of human pituitary adenoma.Material and methodsEighty cases of surgically resected pituitary adenoma specimens were collected from Peking Union Hospital from May 2010 to June 2013. All specimens had been confirmed by clinical and pathlogical diagnosis. The patients were classified histologically as 20 cases of PRL adenoma,20 cases of ACTH adenoma,20 cases of GH adenoma,20 cases of NF adenoma. The age of the patients range from 17 to 58 years old, the average age is 40 years old. Among them 27 cases were from male,57 cases were from female. All patients had not undergone preoperative treatments such as chemotherapy or radiotherapy. According to the Knosp classification,30 cases belong to invasive pituitary adenoma,50 cases belong to noninvasive pituitary adenoma.Using immunohistochemistry, western blot analysis and Real time PCR, we measured STAT3, p-STAT3 and PTTG expression in tumor tissue from patients with pituitary adenoma.Results1. In immunochemistry, STAT3 protein was detected in cytoplasm and nucleus. The score of STAT3 was the highest in GH adenomas (6.15±2.90), as compared with other tumors, including PRL(3.90±2.29), ACTH(3.90±2.29) and NF adenomas(1.85±1.73).The difference between them was most statistically significant (p<0.01).It was of no statistical significance to compare PRL with ACTH adenomas (p=0.57). NF adenomas exhibited the lowest expression levels, thus the comparison with other three tumor subtypes demonstrates a great statistical significance (p<0.05).Above noted results have been confirmed by Western blot analysis.2. In immunochemistry, p-STAT3 protein was detected in nucleus. Score of STAT3 was the highest in GH adenomas(3.20±1.50), as compared with other tumors, including PRL(1.50±1.23), ACTH(1.15±1.39) and NF adenomas(0.85 ±0.74), the difference was statistically significant (p<0.01). Although NF adenomas exhibited the lowest expression levels, there was no statistical significance among PRL, ACTH and NF adenomas (p>0.05). The above noted results have been confirmed by Western blot analysis.3. In immunochemistry, PTTG protein was detected in cytoplasm. Score of PTTG was the highest in GH adenomas (2.05±0.99), as compared with other tumors, including ACTH(1.60±1.05), PRL(1.60±0.75) and NF adenomas(1.40 ±1.05), the difference was statistically significant (p<0.05). Although NF adenomas exhibited the lowest expression levels, there was no statistical significance among PRL, ACTH and NF adenomas (p>0.05). Above noted results have been confirmed by Western blot analysis.4. The expression of STAT3, p-STAT3 and PTTG had no statistical differences in different sex, tumor size and invasiveness(p>0.05).5. STAT3 protein was positively correlated with PTTG protein (rk=0.437, p<0.01). p-STAT3 protein was positively correlated with PTTG protein (rk=0.322, p<0.01)6. STAT3 mRNA 'PTTG mRNA were all detected in PRL,ACTH,GH and NF adenomas and GH adenomas showed a higher expression level.Conclusions1. STAT3 mRNA and protein were all detected in pituitary adenoma.2. Abnormal activation of STAT3 exists in pituitary adenoma.3. The expression level of STAT3, p-STAT3 and PTTG are highest in GH adenoma.4. Activated STAT3 may take function through transcription activation of its downstream target gene PTTG. |
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