The Expression And Clinical Significance Of Notch1?NF-?B?uPA And P-Akt In Colon Adenocarcinoma

Objective:Colorectal cancer is one of the most common malignancies in the world,and the prognosis is poor generally.It is the fifth common cancer-related death^[1?2].In recent years,with the improvement of living standards,the eating style changed greatly:the people took more and more-fat-riched and protein-riched diet,and less and less low fiber diet,such an eating style lead to a significant increase in the incidence of colorectal cancer in China;In other hand,the colorectal cancer usually presented in late clinical stage,and was prone to recurrence and metastasis,resulting in a poor prognosis and no significant decline in mortality of colorectal cancer was reported.Although the widespread use of colonoscopy has help the patients to get the diagnosis at relative early stage of colorectal cancer and a better prognosis,there is no significant improvement in the prognosis for most patients with advanced-stage colorectal cancer,the key lies in that we have not fully understood the pathogenesis of colorectal cancer.Recently,there are more and more studies showed that Notch signaling pathway is involved in various malignant tumors,and be seen as a new hot mechanisms of the pathogenesis of tumor.Notch signaling pathway is a highly conserved signaling system that is closely related to cell proliferation,cell cycle and cell differentiation.It was reported that Notch signaling pathway took part in the regulating of development and differentiation of the intestinal epithelia.Some studies have shown that there was abnormal activation of Notch signaling pathway in colorectal cancer^[3].By extensive review of the literature,it was found that there was crosstalk between the Notch signaling pathway and the PI3K/Akt signaling pathway.From the aboving discussion,we tend to detect the expression and correlation of Notch1,NF-?B,uPA and p-Akt in normal colon mucosa,colon adenoma and colon adenocarcinoma,and to discuss their role and significance in the development of colorectal cancer,and we hope to provide new points into the mechanisms of the colorectal cancer and also hope through this study we can pick out some key molecules that can link different signaling pathway as the new target for the future therapy of colorectal cancer.Method:In this study,We select 141 cases of colon specimens from the Department of pathology,General Hospital Affiliated to Tianjin Medical University during January 2010 and September 2016.Of the 141 cases,86 cases are colon adenocarcinomas among which 33 cases are well-differentiated adenocarcinomas,with a median age of 67 years;39 cases are moderately differentiated adenocarcinomas,with a median age of 74 years;14 cases are poorly differentiated adenocarcinomas,with a median age 68.5 years);25 cases are colorectal adenomas and 30 cases are normal colon mucosa which were removed from the distal cut border of tumor?commonly the distance>5cm from the tumor to the border?as a normal control.The pathologic diagnosis of each specimen was rechecked by a senior pathologist to ensure the accurate diagnosis.Immunohistochemistry staining method of SP was used to detect the expression level of Notch1,NF-?B,uPA and p-Akt in each group.Statistical package SPSS 21.0 was used for data analysis?count data was analied by chi-square test,correlation analysis was analied by Pearson?.Results:1.The expression of Notch1 from normal colon mucosa,colon adenoma to colon adenocarcinoma,the positive rate were 36.67%?11/30?,36.00%?9/25?and 65.12%?56/86?respectively,and the positive rate of Notch1 in colon adenocarcinoma was significantly higher than that of colon adenoma and normal colorectal mucosa?P<0.05?,but there was no significant difference in the positive expression of Notch1between colorectal adenoma and normal mucosa?P>0.05?.2.The expression of NF-?B increased gradually from normal colon mucosa,colon adenoma to colon adenocarcinoma,the positive rate were 30.00%?9/30?,32.00%?8/25?,63.95%?55/86?respectively,and the positive rate of NF-?B in colon adenocarcinoma was significantly higher than that of colon adenoma and normal colorectal mucosa?P<0.05?,but there was no significant difference in the positive expression of NF-?B between colorectal adenoma and normal mucosa?P>0.05?.3.The expression of u-PA increased gradually from normal colon mucosa,colon adenoma to colon adenocarcinoma the positive rate were 23.33%?7/30?,40.00%?10/25?,and 70.93%?61/86?respectively,and the positive rate of u-PA in colon adenocarcinoma was significantly higher than that of colon adenoma and normal colorectal mucosa?P<0.05?,but there was no significant difference in the positive expression of uPA colorectal between adenoma and normal mucosa?P>0.05?.4.The expression of p-Akt increased gradually from normal colonectal mucosa,colon adenoma to colon adenocarcinoma the positive rate were 23.33%?7/30?,36.00%?9/25?,59.30%?51/86?respectively,and the positive rate of p-Akt in colon adenocarcinoma was significantly higher than that of colon adenoma and normal colorectal mucosa?P<0.05?,but there was no significant difference in the positive expression of p-Akt between colorectal adenoma and normal mucosa?P>0.05?.5.Pearson correlation analysis showed that in the colon adenocarcinoma,positive correlation between expression of Notch1 and p-Akt,Notch1 and NF-?B,NF-?B and uPA,p-Akt and NF-?B was found.?the r value were 0.225,0.434,0.751,and 0.683,respectively;all P<0.05?.6.The expression of Notch1,NF-?B,uPA,and p-Akt in colon adenocarcinoma showed a correlation with the tumor differentiation,lymph node metastasis,infiltration depth and Duke's stage?P<0.05?;no correlation was found between the expression of the above 4 markers and the patient's age,gender,and location of the tumor?P all>0.05?.Conclusions:1.The expression of NF-?B,uPA and p-Akt increased gradually from normal colon mucosa,colon adenoma to colon adenocarcinoma,the positive rate of Notch1 in normal colon mucosa is higher than that of colon adenoma and the positive rate of the4 markers in colon adenocarcinoma was significantly higher than that of colon adenoma and normal colorectal mucosa,but there was no significant difference in the positive expression of the 4 markers between colorectal adenoma and normal colorectal mucosa.Such results suggested that the overexpression of these four markers take part in the pathogenesis of colon adenocarcinoma,especially in the late stage from adenoma to adenocarcinoma,they did not show us significant role during the early stage from normal mucosa to adenoma.2.The positive correlation between Notch1 and NF-?B,NF-?B and uPA,p-Akt and NF-?B,Notch1 and p-Akt in colon adenocarcinoma suggested that there may be a crossover between different signaling pathways,they worked together in the pathogenesis of color adenocarcinoma.The crossover between different signaling pathways are mediated by some key molecules such key molecules would provide a new basis for finding new targets for targeted therapy of tumors.3.The expressions of Notch1,NF-?B,uPA and p-Akt in colon adenocarcinoma were correlated with tumor differentiation,lymph node metastasis,depth of invasion and advanced Duke's staging,indicated that these four markers can be used as markers of poor prognosis in the future clinical experience.