| Backgroud Since Thomlisom and Gray found the hypoxic regions in solid tumors,many basic experiments and clinical researches have proved that the tumor’s hypoxia bahavior is due to poor blood vessels within the tumor, which cause the existence of hypoxia and the growth of tumor more invasive. With the development of molecular biology techniques, people have realized that variance of the tumor cell hypoxia is to adapt a series of pathophysiological processes which associate with hypoxia.Recently, scholars consider that mechanisms of enhanced invasion of the tumor are as followes:①ypoxia can inhibit DNA replication of tumor in S phase, When the cells reoxygened, causing excessive DNA replication, on the one hand the results lead to the radiation resistance gene amplification,on the other hand cause chromosome aberration and gene restructuring in tumor cells.②epeated oxygenation can produce oxygen radicals, hydrogen-oxygen radicals can increase the genetic instability, cause mutations of genes,and make the tumor cells more invasive.③ypoxic tumor cells can increase some of the genes and protein synthesis, including the oxygen-regulated protein (ORP, such as heme oxygenase and glycolytic enzymes), vascular endothelial growth factor (VEGF), Erythropoietin (EPO),p53 and platelet-derived growth factor-β(PDGF-P) and so on. Changes in these enzymes or factors is to adapt hypoxia which cause increased tumor aggressiveness and their resistance to treatment.In 1992, Semenza and Wang found that human hepatoma cell line Hep3B and HepG2 cells were treated with 1% hypoxia enviroment, erythropoietin mRNA(EPO mRNA)increased 50 times, when the cells treated by hypoxia, the nuclear extract also promoted the role of EPO gene transcription, but pretreating with protein synthesis inhibitor could block the hypoxic induction of gene expression. then the cell nuclear was extracted by electrophoresis,A kind of protein binding of EPO gene enhancer was found, the protein could activate varieties of hypoxia response genes, it was named as hypoxia inducible factor-1(HIF-1).In 1993, Wang purified of HIF-1 from cultured cells lines Hep3B and HeLaS3and its properties were studied, who proposed that HIF-1 was a physiological regulatorv of gene expression. The tumor icroenvironment is best characterized as a fluctuation of hypoxia and nutrient deprivation, which leads to epigenetic and genetic adaptation of clones and increased invasiveness and metastasis. In turn, these hypoxic adaptations make the tumors more difficult to treat and confer increased resistance to current therapies. Part of this adaptation is the regulation of gene products in response to hypoxia. Many of these hypoxia-regulated genes are mediated by the hypoxia-inducible factor 1 (HIF-1) complex, which is composed of a heterodimerpair of HIF-1αand HIF-1β. When the oxygen concentration is low, the expression of HIF-1αprotein is increased, the cells can produce a series of physiological effects to adapt relative hypoxia by regulating the expression of target genes. Overexpression of HIF-1αprotein has been found in a variety of malignant tumors. Angiogenesis also plays a very important role in tumor growth and metastasis. When the tumor is small in early stage,the angiogenesis provides nutrition for tumor. meanwhile, the newly formed vascular endothelium is not complete, which can provide a channel for the tumor cells into the blood circulation. Process of tumor angiogenesis is Complex, which can be divided into the following six steps:①The tumor produces inducible factors.②The endothelial cells show morphological changes in the induction of factors.③Endothelial cells and tumor cells release proteases which can degradate capillary basement membrane and extracellular matrix, in order to remodeling extracellular matrix.④ndothelial cells postcapillary venule migrate and form blood vessels sprout.⑤)Endothelial cell proliferates, vascular sprouts extend. The tumor angiogenesis and metastasis can be inhibited by blocking several key points.Therefore, anti-angiogenic research can provide a new strategy for the present treatment of the tumor which have certain clinical significance.Objective For reveal the roles and clinical significance of hypoxia inducible factor-1 alpha (HIF-la) and micro vessel density (MVD) in the human prostatic disease, We study the distribution of HIF-la,MVD in prostate by immunohistochemistry and statistics percent of colour positive cell to compare difference among prostatic carcinoma,high-grade prostatic intraepihtelial neoplasia, benign prostatic hyperplasia and normal prostatic tissue.Methods To collect 55 conventional paraffin wax tissues of prostatic carcinoma,high-grade prostatic intraepihtelial neoplasia and benign prostatic hyperplasia from our hospital from september 2006 to june 2010,The normal prostate corned from corpse. Immunohistochemical technique was applied to detect the expression of HIF-la and MVD in routinely processed tissue specimens from human prostatic carcinoma and hyperplasia.All tissues were fixed by formalin,its concentration is 10 percentage.Fixed time is between eighteen hours and twenty-four hours. Specimens were embedded by ozocerite and chip to Sum thickness.One specimen was HE stain, another was HIF-la and MVD immunoreactivity.Positive staining of tumor tissue was positive constrast and PBS replaced first antibody was negative.Positive matter was found in cytolymph or nucleus and its colour was brown. Judgement standard is percentage of positive cell.The destination was to study the characteristic of HIF-la and MVD in prostate by inmunohistochemistry and statistics percentage of colour positive cell to compare difference to prostatic carcinoma,high-grade prostatic intraepihtelial neoplasia, benign prostatic hyperplasia and normal prostate.Results The percentage of positive cells of hypoxia inducible factor-1 alpha was shown followed:PC 73.13±8.57,HGPIN 64.53±14.49,BPH 22.93±12.58,NP O.According to pathlolgical grade, The percentage of positive cells of hypoxia inducible factor-1 alpaha was shown as follow:high grade 62.34±6.35,moderate-grade 70.93±2.88,low-grade 79.95±4.90. According to clinical stage, The percentage of positive cells of hypoxia inducible factor-1 alpha was shown as follow:Ⅰ+Ⅱ65.31±6.43,Ⅲ+Ⅳ77.67±6.02; The mean MVD count was shown as followed:PC 62.13±9.22,HGPIN 35.20±9.69,BPH 23.53±7.60,NP 16.00±5.16. According to pathlolgical grade,the mean MVD count was shown as follow:high grade 50.57±4.58,moderate-grade 60.44±4.19,low-grade 69.00±6.68. According to clinical stage, the mean MVD count was shown as follow:Ⅰ+Ⅱ53.82±6.08,Ⅲ+Ⅳ66.95±7.06;The differences were statistically significant in groups both of various pathological grade and clinical stage (P<0.05). And there was positive correlated between HIF-la positive expression and MVD(r=0.835,P<0.05).Conclusion1. HIF-la and MVD may play an important role in the and the development of prostatic disease. The expression of HIF-1αand MVD change from low to high in the process from normal prostate to prostatic hyperplasia and prostatic tumor.HIF-la and MVD are functional and may represent the molecular basis of prostatic disease, as well as a potential new target for the diagnosis and therapy of adrenal disease. 2. Overexpression of hypoxia inducible factor-1 alpha and MVD count is closely related to tumor’s clinical progression,and they can be used as an important prognostic factor.3.Overexpression of hypoxia inducible factor-1 alpha is the preliminary incident of the formation of prostatic carcinoma,which may induce carcinoma into malignant phenotype.Thus it may be the eary diagnosis parameter and novel target for prostatic carcinoma treatment. |
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