The Expression And Clinical Significance Of RAGE, S100A8 And S100P In BPH And Prostate Cancer Tissues

PC(prostate cancer) is one of the common malignant tumors in male genitourinary system. It has been found around the world that the incidence of PC ranks the second among the male malignant tumors with its mortality ranking the sixth[1]. PC incidence is extremely high in Europe and America and at present, PC incidence even exceeds lung cancer incidence in America, thus becoming the No.1 tumor endangering male health[2]. In Asia, PC incidence is far lower than that in Europe and America but in recent years, PC incidence has been on the rise in Asian countries with a much faster growth than that in Europe and America. According to the newly released data from the National Cancer Center, it was found that since 2008, PC has become the tumor with the highest incidence in the urinary system in China with PC incidence ranking the sixth among the male malignant tumors and its mortality ranking the ninth[3,4]. Besides, according to a worldwide survey carried out in 2012, it was found that PC rose significantly in China. Specifically speaking, PC incidence had an annual growth of 2.1% from the year 1988 to 1994 while from the year 1994 to 2002, PC incidence had an annual growth of 13.4%[1].In the past decade, scholars both at home and abroad made a large number of fruitful explorations on PC pathogenesis, however, PC pathogenesis is still unclear. At the early stage of PC, most of the clinical symptoms are latent and most PC cases are discovered only after the patients receive TURP(transurethral resection of prostate) or open surgery but at that time, most patients are already at the middle or late stage of PC with the best time for radical treatment being missed. At present, PC screening mainly depends on PSA(prostate-specific antigen). However, in recent years, apart from PSA, other tumor markers were also found to be of potential diagnostic value such as the marker PCA3 which has been approved by US Federal Drug Administration(FDA) in the diagnosis of PC. For patients with a high PSA, PCA3 could produce a more accurate diagnosis of PC[5、6]. Evenso, those molecular markers display a lack of specificity to some extent, which would cause missed diagnosis. Nowadays, the major therapeutic methods of PC include radical surgery therapy, endocrine therapy, chemotherapy and radiation, etc. Endocrine therapy is often preferable to patients with local recurrence or distant metastasis after treated by radical surgery or to patients who have lost the opportunity of surgical therapy. However, endocrine therapy only proves effective at the early stage and later patients would gradually develop CRPC(castrate-resistant prostate cancer) which makes the treatment extremely difficult. Thus, it has become a research hotspot both at home and abroad to screen out a high sensitive index to assist early PC diagnosis at molecular level and find a new target for PC treatment.The occurrence, development and metastasis of tumor is a complicated process with multiple factors, multiple steps and multiple genes involved and molecular pathological changes such as gene mutation, proto-oncogene activation, anti-oncogene inactivation and a series of resultant signal pathway abnormalities, etc. run though the whole stage of tumor lesion. At present, the PC pathogenesis and the molecular biological basis of PC occurrence and development is still unclear. According to previous studies, the occurrence and development of PC was related to many processes such as inactivation of wild-type anti-oncogenes p53, p16, PTEN, ran23, NKX3.1, Rb, etc., abnormal expression of cancer genes c-myc, c-met, bcl-2, ras, etc., polymorphism of AR, PSA, VDR, etc., and DNA methylation, etc. However, studies in recent years show that PC is closely related to RAGE(receptor for advanced glycation end products) and S100.RAGE(receptor for advanced glycation end products) is one member of the immune globulin family. As a multiple-ligand transmembrane receptor, RAGE could activate multiple signal transduction mechanisms within the cell through the combination with various ligands on the cells’ surface and it could also participate in many biological effects such as diabetes-related chronic complications, inflammatory reaction, nerve regeneration, Alzheimer disease, DRA(dialysis-related amyloidosis), atherosclerosis, the growth, invasion and metastasis of tumors, etc[7,8]. According to previous studies, it was found thatthere was high RAGE expression in multiple tumor tissues such as liver cancer, stomach cancer, pancreatic cancer, etc. but low RAGE expression in rhabdomyosarcoma and lung cancer[9-13]. The abnormal expression of RAGE is closely related to such factors as the occurrence of tumor, angiogenesis, and the degree of invasion and metastasis. S100 protein is composed of at least 20 proteins with calcium adhesion ability including S100A8 and S100 P and it has been found that S100A8 and S100 P display expression in multiple tumor tissues such as stomach cancer, colorectal cancer, etc[14,15]. Through the combination with the ligands S100A8 and S100 P, RAGE plays an important role in the occurrence, development, invasion and metastasis of tumors. Thus, it is highly probable that RAGE and its ligands S100A8 and S100 P will become the molecular marker and potential new target for tumor treatment.It was found in large quantities of previous studies that RAGE participated in the occurrence, development, invasion and metastasis of various tumors through the combination with its ligands S100A8 and S100 P. However, there are very few reports on the relationship between RAGE and its ligands S100A8 and S100 P and PC clinical pathologic parameters at home.Objective:In the present research, the author tries to explore the expression of RAGE and its ligands S100A8 and S100 P in BPH and PC tissues and then analyze the differences in the expression. The author would also explore the relationship between the expression of RAGE and its ligands S100A8 and S100 P and clinical pathologic parameters. Finally, the author would like to explore the possibility of taking RAGE and its ligands S100A8 and S100 P as the molecular marker for PC diagnosis, treatment and prognosis by making an analysis of the role of RAGE and its ligands S100A8 and S100 P in the occurrence, development, invasion and metastasis of PC, the correlation among the expressions of RAGE and its ligands S100A8 and S100 P in PC tissues, and the relationship between RAGE and its ligands S100A8 and S100 P and the biochemical recurrence of PC patients.Method:In the present research, 32 patients were selected and those patients either received rectal ultrasound guided prostate biopsy during the period from October, 2012 toFebruary, 2015 or were diagnosed as PC after surgery. Besides, another 30 patients who were diagnosed as BPH at the same period were randomly selected as the control group. All the pathological tissues received HE staining and after the diagnosis, immunohistochemical method(Envision two steps method) was employed to examine the tissues of 30 BPH patients and the expression of RAGE and its ligands S100A8 and S100 P in 32 PC patients. Then light microscope was employed to observe immunohistochemical staining with the staining results being analyzed. A follow-up visit to the patients who received surgery was also conducted to learn biochemical recurrence of PSA. Then 18 patients who received RP(radical prostatectomy) met the requirement and received follow-up visit. The follow-up visit was carried out once every three months and it lasted from three months to twenty seven months with an average follow-up time of thirteen months. All the data were processed with SPSS19.0 statistical software. X2 test was employed to analyze the different expressions of RAGE and its ligands S100A8 and S100 P in BPH and PC tissues. Fisher’s exact test was employed to explore the relationship between the expressions of RAGE and its ligands S100A8 and S100 P and PC patients’ clinical pathologic parameters(age, PSA, Gleason mark, TNM-staging). Spearman rank correlation analysis was employed to explore the correlation among expressions of RAGE and its ligands S100A8 and S100 P in PC tissues. Finally, Kaplan-Meier survival analysis was employed to explore the relationship between RAGE and its ligands S100A8 and S100 P and PC patients’ biological recurrence.Result: ① RAGE and its ligands S100A8 and S100 P displayed expression location in BPH and PC cells. Specifically speaking, most RAGE was located in the cytoplasm with a small amount in the cell membrane, most S100A8 was locate in the cytoplasm with a small amount in the cell membrane, most S100 P was locate in the cytoplasm with a small amount in the cell membrane and nucleus.② The positive expression rates of RAGE in BPH and PC tissues are 33.3%(10/30) and 68.7%(22/32) respectively(P=0.005). The positive expression rates of S100A8 in BPH and PC tissues are 23.3%(7/30) and 62.5%(20/32) respectively(P=0.002). Thepositive expression rates of S100 P in BPH and PC tissues are 30%(9/30) and 65.6%(21/32) respectively(P=0.005). It was found that there was statistical significance among the different expressions of RAGE and its ligands S100A8 and S100 P in BPH and PC tissues.③ It was found that expressions of RAGE and its ligands S100A8 and S100 P were independent from PC patients’ age and Gleason mark. Expressions of S100A8 and S100 P were independent from patients’ PSA levels before surgery while expression of RAGE was correlated with patients’ PSA levels before surgery(P=0.049). Besides, expressions of RAGE and its ligands S100A8 and S100 P were correlated with PC patients’ TNM-staging(P=0.005、P=0.004、P=0.002), N-staging(P=0.024、P=0.008、P=0.011), M-staging(P=0.019、P=0.028、P=0.008).④ It was found that there was a positive correlation relationship between RAGE expression and S100A8 expression(P=0.000) with a correlation coefficient of 0.592(r=0.592) and there was also a positive correlation relationship between RAGE expression and S100 P expression(P=0.000) with a correlation coefficient of 0.648(r=0.648).⑤ It was found that between patients with co-expression of RAGE and S100A8 and non co-expression patients, there was statistical significance in PC biological recurrence(P=0.004) and between patients with co-expression of RAGE and S100 P and non co-expression patients, there was also statistical significance in PC biological recurrence(P=0.02).Conclusion ① The expressions of RAGE and its ligands S100A8 and S100 P in PC tissues were significantly higher than those in BPH, which shows that RAGE and its ligands S100A8 and S100 P were all related to PC.② The expressions of RAGE and its ligands S100A8 and S100 P were related to PC patients’ clinical stages and with PSA level getting higher, RAGE expression also increased, which shows that RAGE and its ligands S100A8 and S100 P were likely to have participated in the development, invasion and metastasis of PC and thus accelerated PC development.③In the PC tissues, RAGE expression was positively correlated with both S100A8 expression and S100 P expression. Combining with the results from past studies, it can be found that in the PC tissues, RAGE could exert cooperative induction after combining with the specificity of S100A8 and S100 P, so it could promote tumors’ development. Thus, RAGE and its ligands S100A8 and S100 P are expected to become a new target for PC treatment.④It was found that patients with co-expression of RAGE and S100A8 were more likely to develop biological recurrence than non co-expression patients and patients with co-expression of RAGE and S100 P were also more likely to develop biological recurrence than non co-expression patients since under the condition of co-expression, PC development was accelerated under the forces of two molecules. Thus, co-expression is expected to become a molecular marker for PC prognosis.