Expression Of Tyrosine Phosphatase Containing C-Src Homology SH-2 In Benign Prostate Hyperplasia

Many important cellular physiological functions , such as cell survial, growth, differentiation, metabolization, adaption, defence and apoptosis, are highly controlled by the intracellular signal transduction processes in which protein tyrosine phosphorylation and dephosphorylation are central events. Protein tyrosine phosphatase (PTP) can dephosphorylate the phosphotyrosine specially in cell. It is related to cellular growth and differentiation, which obstruction is just one of the characters of tumor. SHP-2, a Src homology (SH)2 domain-containing protein tyrosine phosphatase(PTP), is ubiquitously expressed in various tissues and cell lines. It is widely involved in a variety of signaling pathways triggered by cytokines and growth factors, including the MAP kinase, Jat-Stat, and PI3 kinase pathways. The deregulated activity of SHP-2 has been demonstrated to contribute to the development of several human disorders, including diabetes, condyloma acuminatum, leucocythemia, mammary adenocarcinoma, etc.Benign prostate hyperplasia(BPH) is the most common benign neoplasm for elderly patients. BPH patients and PIN (Prostate Intraepithelial Neoplasia) patients got high-risk for prostate carcinoma. Prostate cancer (Pca) become the secondcause of death of men in west. About the pathogenesy of BPH, there are many doctrines including hormone-incretion theory, growth factor theory, epithelium-stroma cell reciprocity theory , cell apotosis and gene regulation theory, which is associated with signal transduction processes. Many cytokines and growth factors regulated cell survival and apoptosis are mediated through signal transduction processes as ras-MAPK pathway leading from receptor. It is never reported abroad about the expression in BPH. It may lay a basis for future study of finding new agents targeting (inhibition to) signaling pathway in BPH by investigating the mechanism of BPH.We detected the distribution of P-Tyr, SHP-1 and SHP-2 in order to study the expression of P-Tyr, SHP-1 and SHP-2 in BPH tissue by immunohistochemistry, so as to further understanding the significance of SHP-2 in signaling pathway in BPH.Materials and MethodsProstate tissues were obtained from 15 patients with BPH, 10 patients with PIN, 10 patients with high differential Pea and 10 patients with low differential Pea. These were another 5 normal tissues as control group. These tissues satisfied the test standard of Histologic typing (WHO 2002). Expression and distribution of P-Tyr, SHP-1 and SHP-2 in prostate tissue were detected by immunohistochemistry method. Immunohistochemistry was performed using monoclonal antibody against P-Tyr (PY-99), SH-PTP1 (D-ll), SH-PTP2 (B-l). Envison two-step was employed to detect P-Tyr, SHP-1 and SHP-2 on these cases.Test results judgment: Membrane, cytoplasm or nucleolus of prostatic basal cell or epithelium cell stained were regarded as positive. According to the percentage of the positive cells and stain degree, the semiquantitative analysis was carried out to grade it. Statistical analysis were performed with Fisher's exactprobabilities method. Statistical comparisons between experimental groups were performed with t-test and the relative analysis was performed with Kendall's tau-b method.Results1. Expression of P-Tyr. No-expression of P-Tyr were shown in normal prostate tissues. The expression of P-Tyr strengthened according to the severity of the illness in BPH, PIN and Pea. The expression mainly distributed in the cytoplasm of secretive cells and basal cells. Some P-tyr expression was observed on the membrane of secretive cells also.2. Expression of SHP-1. Immunohistochemical analysis of SHP-1 positive expression in normal prostate, BPH, PIN and high differential Pea showed differentiating layer staining in the cytoplasm of secretive cells and basal cells, while not in low differential Pea.3. Expression of SHP-2. Immunohistochemical compare of SHP-2 positive expression in normal prostate, BPH, PIN and high differential Pea showed differentiating layer staining in the cytoplasm of secretive cells and basal cells.4. The relationship between the distribution of SHP-2 in prostate and the type of illness. The expression of SHP-2 in normal and BPH cell mainly distributed in the cytoplasm, while the expression in PIN and Pea mainly in the nucleolus. The distribution of SHP-2 in human prostate transfer to nucleolus significantly with cell differentiation.5. In 50 cases of experimental and control group, we compared the expression ofSHP-1 and SHP-2, we found that there was negative correlation between the expression of SHP-1 and SHP-2(r= -0.296,p<0.01).Conclusions1. The tyrosine phosphorylation was significantly stronger in BPH group than in normal group, and stronger in Pea group than in BPH and PIN group. It suggests that the tyrosine phosphorylation get stronger during the prostate cell proliferation, differentiation and transformation.2. Expression of SHP-1 were strong in normal, BPH,PIN and high differential Pea, while weak or negative in low differential Pea. It suggests SHP-1 might regulate negatively during the proliferation, differentiation and transformation of prostate cell.3. Expression of SHP-2 get stronger in normal, BPH, PIN and Pea during proliferation, differentiation and malignant, with the distribution transfer from cytoplasm to nucleolus. It suggests the abnormal activation of SHP-2 might induce prostate reconstruction and hyperplasia, the transfer of distribution might be an important guideline of malignancy.4. There was negative correlation between the expression of SHP-1 and SHP-2.We hypothesis that in the progress of cell proliferation, differentiation and malignant, SHP-1 and SHP-2 keep homeostasis. If the homeostasis was broken it might result in diseases and carcinoma further.