The Expression And Clinical Significance Of RAGE And HMGB1in Benign Prostatic Hyperplasia And Prostate Cancer Tissues

Prostate cancer is the one of the most common malignant tumor in male genitourinary system, particularly in the developed countries. In United States, of the more than700,000new cases of cancer occurring in men each year, approximately one third or230.000new cases were expected to be cancer of the prostate in2005. Based on the GLOBOCAN2008estimates, prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in males, accounting for14%(903.500) of the total new cancer cases and6%(258,400) of the total cancer deaths in males in2008. At present, the incidence of prostate cancer in China is much lower than that of the developed countries. But as the aging of the population, the change of diet, the environment pollution alongside the improvement detection of prostate cancer such as a test for PSA, the incidence of prostate cancer in China has shown a steep increase in recent decades.At present, the pathogenesis of prostate cancer is still complex. Because the symptoms of early stage for prostate cancer is non-specificity, most of time is no symptom. Most of time, patients are diagnosed of late stage of prostate cancer, and thus lose the chance for radical therapy. At present, screening prostate cancer rely mainly on the PSA (prostatic specific antigen). However, the currently used biomarker PSA for prostate cancer is unsatisfactory. A part of patients of prostate cancer, the PSA levels in serum are low, leading to missed diagnosis for prostate cancer. As we known, radical therapy is the most effective method for prostate cancer, but some of radical treatments in patients with early stage of prostate cancer still have the chance for recurrence. Treatment for advanced prostate cancer rely mainly on the endocrine therapy, but it hardly can avoid to develop to hormone independent prostate cancer and hormone refractory prostate cancer. Therefore, it is important in seeking new biomarkers that are able to reflect biological activities and are able to be used in diagnosis, prognosis and treatment of prostate cancer.Nowadays molecular biology is the hot research of cancer. The formation and molecular biology of prostate cancer is still unclear. A number of studies have demonstrated that prostate cancer correlated with the chromosomal abnormality of human8p chromosome, the activation and up-regulation of proto-oncogene, including Bcl-2、Fos、c-myc、c-met、ras, the inactivation of anti-oncogenes, including p53、Rb、p16、PTEN、CDKN2、the polymorphism of genes and the methylation of DNA. Recently, new studies suggested that RAGE and its ligand HMGB1were associated with formation and progression in prostate cancer.RAGE is a member of immunoglobulin superfamily of receptors and has properties that make it a key role in a variety of diseases, including diabetes chronic complications. RAGE can expression in many tissues and cell types, usually at low expression in homeostasis except in the lung. About ten years ago, the important role of RAGE in cancer began to be appreciated. Many studies have demonstrated that expression of RAGE is up-regulation in many cancers except lung cancer. And it is associated with invasion, metastasis and poor prognosis. HMGB1is the most important ligand of RAGE in cancer. HMGB1is nonhistone DNA-binding protein. HMGB1is over-expression in all tumors. Research demonstrate that the interaction of RAGE and HMGB1can activate a variety of cell signaling that regulate important cancer cellular function, including proliferation, invasiveness and migration. Therefore. RAGE and HMGB1are potential targets for prostate cancer diagnosis and therapy.In recent years, most studies have demonstrated that the interaction of RAGE and its ligand HMGB1have been implication in the development, invasion and metastasis of cancer. However, none of these studies demonstrated the relationship between RAGE/HMGB1expression and clinicopathologic parameters in patients with prostate cancer. The study on the correlation of between RAGE/HMGB1expression and the survival analysis in prostate cancer also cannot be found.Objective:The aim of this study was to investigate the expression of RAGE and HMGB1in benign prostatic hyperplasia (BPH) and prostate cancer, and then analyze their correlation with the disease. To explore the relationship between RAGE/HMGB1expression and the clinicopathologic parameters. Retrospectively analyze RAGE and HMGB1protein expression and their co-expression with the survival time of patients with late stage of prostate cancer, in order to provide basis for clinical prognosis. To further explore the involvement of RAGE/HMGB1in the development, invasion, and metastasis of prostate cancer. And explore the feasibility that RAGE/HMGB1as new biologic markers for diagnosis, prognosis and treatment for prostate cancer.Methods:Eighty-five patients with prostate cancer with well-document clinicopathologic data, who were underwent surgery or biopsy from2003to2009, were enrolled in this study. And thirty cases diagnosed benign prostatic hyperplasia in the same period were randomly chosen as control. Hematoxylin and eosin stained slides were preformed in all cases and then re-confirmed the diagnosis by pathology. The expression of RAGE and HMGB1in85prostate cancer and30benign prostatic hyperplasia were assessed by immunohistochemistry. The result of immunohistochemical staining were observed by light microscope, and then make analysis. SPSS13.0software was employed for statistical analysis. Chi-square test or Fisher’s exact test was used to analyze the association of expression of RAGE and HMGB1in BPH and prostate cancer. The correlation between expression of RAGE and HMGB1and clinicopathological features (age, PSA, Gleason score, TNM staging) of patients with prostate cancer was analyzed with a Chi-square test or Fisher’s exact test. Spearman rank correlation analysis was used to analyze the correlation of RAGE and HMGB1expression in prostate cancer. Kaplan-Meier method was used to estimate overall survival according to RAGE, HMGB1and their co-expression in patients with clinical stage III and IV of prostate cancer, and the differences were estimated with the log-rank test, and for multivariate. Cox proportional hazard regression model was used.Results:①In prostate cancer and BPH tissues, RAGE staining was detected predominantly in the cytoplasm, and a minor part in membrane, and HMGB1IHC signals were localized in the nucleus widely, others in cytoplasm.②The positive expression of RGAE was in46.7%(14/30) of BPH and78.8%(67/85) of prostate cancer. HMGB1expression was positive in68.2%(58/85) of prostate cancer and in33.3%(10/30) of BPH. The expression of RAGE and HMGB1was significant difference between benign prostatic hyperplasia and prostate cancer (P=0.001).③The co-expression of RAGE and HMGB1was in13.3%(4/30) of BPH and63.5%(54/85) of prostate cancer. The co-expression of RAGE and HMGB1was significant difference between benign prostatic hyperplasia and prostate cancer (P=0.000).④The expression of RAGE and HMGB1was significantly associated with T stage, N stage and distant metastasis. Further, RAGE expression showed a correlation with PSA level (P<0.05). Both of RAGE and HMGB1expression was not significantly related to the age and Gleason score.⑤The co-expression of RAGE and HMGB1also showed a significant positive correlation with T stage (P=0.007), N stage (P=0.002) and distant metastasis (P=0.026), whereas no relationship was found with PSA level, including Gleason score and age.⑥The correlation of RAGE and HMGB1expression was positive correlation (P=0.000). The correlation coefficient is0.511.⑦Patients with clinical stage III and IV of prostate cancer were followed up. There was statistically significant difference in overall survival rates according to the co-expression of RAGE and HMGB1. However, both of RAGE and HMGB1did not show an association with overall survival rates independently. Distant metastasis was a prognostic factor in patients with prostate cancer by multivariate analyses.Conclusions:①The expression RAGE, HMGB1and their co-expression were significantly higher in prostate cancer than in the benign prostatic hyperplasia. The result suggests that RAGE and HMGB1play an important role in formation of prostate cancer. RAGE and HMGB1may be server as new markers for diagnosis of prostate cancer.②The expression RAGE, HMGB1and their co-expression were significantly associated with organ-confined, lymph node metastasis, distant metastasis, The result suggests that the interaction of RAGE and HMGB1promote the development, invasion and metastasis of prostate cancer. ③The expression of RAGE was positive correlation with HMGB1protein expression in prostate cancer. The result suggests that RAGE can bind HMGB1in prostate cancer and promote cancer development. RAGE/HMGB1may as the potential target for treatment in prostate cancer.④The patients with co-expression of RAGE and HMGB1had a significantly poorer prognosis than those not co-expression of RAGE and HMGB1in overall survival rate. The result suggests that the interaction of RAGE and HMGB1play an important role in progression of prostate cancer. And result in shortening the survival time of patients with prostate cancer. Detection of RAGE/HMGB1may help in predicting recurrence and prognosis for patients with prostate cancer.