S100P Clinical Significance Of Abnormal Expression In Colorectal Cancer And Its Regulatory Mechanism

Background:Colorectal cancer(CRC) is one of the most common types of malignant tumors worldwide.In China,CRC is the 4th leading cause of cancer-related mortality.Although great advances have been made in the diagnosis and treatment of this cancer,the survival rate of CRC patients is not improved profoundly.It has important clinical significance to put insights into the molecular mechanism of CRC and to search for the ideal markers for the early diagnosis and prognosis.In recent years,researchers has paid close attention to S100P,which has abnormal expression in many tumors and may contribute to the growth,infiltration and metastasis of tumor cells.The expression of S100P is related to the diagnosis or prognosis in some tumors.It has not been identified,however,the clinical value of the high expression of SIOOP in CRC.Objective:To identify the clinical significance of S100P high expression in CRC tissue,and to investigate Epigenetic mechanisms of S100P expression. Moreover,the serum level of S100P in CRC and its clinical value is to be studied.Methods:The postoperative tumor tissue samples and their paired normal colorectal tissue from 96 patients and preoperative serum specimens from 76 patients with sporadic CRC in our hospital were collected from July 2003 to July 2006.The clinical pathologic data of these patients were integrated,with the follow-up period of 30 to 65 months.Western blot and real-time quantitative reverse-transcription PCR were performed for detecting the expression of S100P protein and mRNA in CRC tissue and in colorectal cancer cell lines.The data of the expression of S100P protein and mRNA were analyzed and correlated with the clinical pathologic information.The correlation of S100P promoter region methylation and S100P gene expression was identified by Bisulphite Sequencing PCR(BSP).The method of fluorescence real time Quantitative Methylation Specific PCR(QMSP) was set up to detect the methylation state of S100P promoter region in CRC tissue and in colorectal cancer cell lines.The date from BSP and QMSP were then correlated with the S100P gene expression and clinical data.Enzyme linked immunosorbent assay(ELISA) was used for detecting the serum level of S100P in patients with CRC and normal controls.The results were correlated with the clinical data to evaluate the diagnosis and prognosis value of the preoperative serum S100P level in patients with CRC.Results:Of 96 patients with sporadic CRC involved in this study,61 were males and 35 were females,including 29 right hemicolon cancers,17 left hemicolon cancers and 50 rectal cancers.The average age was 62.4±1.2 years.63.0%(51/81) of CRC tissue express S100P protein,significantly higher than the paired control group(4.9%,P=8.13×10^-15).The expression of S100P mRNA in CRC tissue is also significantly higher than the paired normal group(P=0.005).The methylation state of S100P promoter region detected by BSP was strikingly correlated with the expression of S100P mRNA(P=0.002, 0.039,respectively) in colorectal cancer cell lines and tissue.A similar result was obtained through fluorescence real time QMSP in colorectal cancer cell lines and tissue(P=0.001,5.0×10^-6,respectively).The expression of S100P protein in CRC tissue has significant correlation with the primary cancer location.The expressing rate of S100P protein in CRC was 42.3%for right hemicolon,61.5%for left hemicolon,and 76.2%for rectum. The similar relation was not shown between the expression of S100P protein and the clinical stage.However there was no notable correlation between the expression of S100P mRNA and the clinical features of CRC such as primary cancer location and clinical stage.The quantitation of the methylation state of S100P promoter region was significantly higher in rectal cancer than in colon cancer(P=0.007),which also had a gradual downward trend according to the decrease of the tumor differentiation degree(P=0.098).In the CRC patients from stageⅠto stageⅢ,a tendency was shown that the prognosis of patients with S100P protein expression was better than that without expression(P= 0.056).The preoperative serum level of S100P in CRC patients is significantly higher than normal controls.The sensitivity of serum S100P level for diagnosis of CRC was 38.2%and the specificity was 91.9%compared with the healthy people.Combined test of serum S100P and CEA in CRC had a positive rate up to 64.4%.The preoperative serum S100P level in CRC patients had a tendency to increase as the cancer clinical stage progressing(P=0.050).The positive rate of serum S100P in each stage of CRC was stageⅠ25.0%,stageⅡ30.8%,stageⅢ44.4%and stageⅣ54.5%.The preoperative serum level of S100P was an independent factor of long - term survival(P=0.023) in CRC patients.The 5-year cumulative survival rate of patients with a high preoperative serum S100P level was 52.3%,and the 5-year cumulative survival rate of patients with a normal serum S100P level was 81.4%(P=0.005). If adjusted the influence of clinical stage,the CRC patients with elevated preoperative serum S100P had a 3.6 times increase in the risk of death comparing with those with normal serum S100P levels.Conclusions:The expression of S100P protein and mRNA in CRC tissue is significantly higher than the paired normal colorectal tissue.The expression of S100P protein is notably correlated with the primary cancer locations,and also has a negative correlation with survival of CRC patients.In some degree,the methylation state of S100P promoter region may regulate the expression of S100P.The preoperative serum S100P level in CRC patients is significantly higher than that in normal controls.Preoperative elevated serum S100P level correlates with a poor prognosis in CRC patients.Combined test of serum S100P and CEA can increase the sensitivity of diagnosis in CRC.