Expression And Clinical Significance Of AEG-1、β-catenin And LEF-1 In Human Colonic Carcinoma

BackgroundColon cancer is one of the most common gastrointestinal cancer,its incidence and mortality showed an increasing trend,about 60 million people die of colon cancer each year in the world. The incidence of colon cancer is the result of the external environmental factors and the body’s internal factors, external environmental factors like exposing to carcinogen and developing bad habits(such as diet, smoking, etc), internal factors such as inactivation of tumor suppressor genes and mutated oncogenes, leading to uncontrolled cell growth and tumor formation.Its occurrence, development and evolution is a multi-step, complexed biological processe involving in the abnormal expressions of many genes in the key signaling pathways. The main treatment of early colon cancer is surgery, supplemented by chemotherapy and radiotherapy, but many patients were advanced when diagnosed; the treatment in advanced colon cancer is not ideal. Studying the molecular mechanism of colon cancer has a very important role in the their diagnosis, treatment and prognosis.Astrocyte elevated gene-1(AEG-1)(also known as MTDH) was originally induced in primary human fetal astrocytes infected with HIV-1 or treated with either HIV gpl20 or TNF-a. It has been identified as a proto- oncogene in recent years and found to promote cancer proliferation, invasion, metastasis, angiogesis and chemoresistance. Recently, people have revealed that AEG-1 is overexpressed in various malignancies, the gene can activate PI3K/Akt、Wnt/β-catenin、NF-κB signaling pathway to promote the occurrence and progressionin of the tumor.β-catenin is a multifunctional protein and widely present in the cell membrane, cytoplasm and nucleus. Under normal circumstance, β-catenin in the cell membrane connecting with cadherins form an adhesive tape,it is an important cell adhesion molecules and cytoskeletal protein. As the key mediated factor in the Wnt signaling pathway, its abnormal expression can be an activation indicator in Wnt signal transduction pathway.LEF-1 is an important nuclear transcription factor in the Wnt signaling pathway and plays the role as the molecular switch in the regulation of transcription.It activates the Wnt signaling pathway through recruiting β-catenin and forming β-catenin- LEF / TCF complex.It works in tumor proliferation, differentiation, invasion and metastasis mainly through its mediated signaling pathways. ObjectivesTo study expression of AEG-1, β-catenin and LEF-1 in colon cancer and to analyse its clinical significance. Materials and Methods1.78 colonic carcinoma tissues and 78 matched paratumours normal colon tissues(more than 5cm from the distal colon)by anorectal and gastrointestinal surgical removal and pathologically proven,which were collected from in First Affiliated Hospitalof Zhengzhou University. All specimens were neutral formalin –fixed and paraffin-embedded.All cases of colonic carcinoma patients were not receiving preoperative chemotherapy,radiotherapy,or biological targeted therapy. 44 males and 34 females of colonic carcinoma patients; aged 35-76 years(mean age 55 years); primary site: 33 cases of left colon, 45 cases of right colon; there are 46 cases well-differentiated and 32 cases poorly differentiated by pathological grading; 35 cases without lymph node metastasis, 43 cases with lymph node metastasis; there are 59 cases without distant metastasis and 19 cases with distant metastasis by distant metastasis.2. Immunohistochemistry was used to examine expression of AEG-1、β-catenin and LEF-1 in colonic carcinoma and matched paratumours normal colon tissues. Analysis the correlation among them and the clinical pathologic factors,and the significance of the three indicators were explored in the occurrence and development of colonic carcinoma.3.Statistical analysis All the data were analyzed by SPSS 17.0 software. Differences among groups were analyzed by chi-square test. The correlation of AEG-1、β-catenin and LEF-1 was analyzed by Spearman rank correlation, Test level a=0.05. Results1. The expression of AEG-1The positive expression of AEG-1 is mainly located in cell membrane or/and cytoplasm. The positive rate of AEG-1 in human colonic carcinoma was 73.1%(57/78),which was significantly higher than that in paratumours normal colon tissues 24.4%(19/ 78), the difference was statistically significant(χ2=37.05 P<0.001); AEG-1 expression was related with tumor cell differentiation(χ2=5.737 P=0.017), lymph node metastasis(χ2=5.518 P=0.019),distant metastasis(χ2= 5.990 P=0.014), and stage(χ2= 6.673 P=0.010).2. The expression of β-cateninThe abnormal expression of β-catenin is mainly located in cell cytoplasm and(or)nucleus. The abnormal expression rate of β-catenin in human colonic carcinoma was 82.1%( 64/78),which was significantly higher than that in paratumours normal colon tissues 30.8%(24/78),the difference was statistically significant(χ2=41.71 P<0.001);β-catenin expression was significantly associated with lymph node metastasis(χ2=4.865 P=0.020),distant metastasis(χ2=9.953 P=0.002), and stage(χ2=4.808 P=0.028).3.The expression of LEF-1The positive expression of LEF-1 is mainly located in the nucleus, the minority in the cytoplasm. The positive rate of LEF-1in human colonic carcinoma was 67.9%(53/78),which was significantly higher than that in paratumours normal colon tissues 21.8%(17/78),the difference was statistically significant(χ2= 33.58 P<0.001);LEF-1 expression was significantly associated lymph node metastasis(χ2=5.442 P=0.020),distant metastasis(χ2=5.344 P=0.021), and stage(χ2=1.139 P=0.001).4. The correlation analysis of AEG-1、β-catenin and LEF-1 expression in colonic carcinoma tissuesSpearson correlation analysis showed that the AEG-1 expression was positively correlated with β-catenin expression(r=0.243, P=0.032). Also, the AEG-1 expression was positively correlated with LEF-1 expression(r=0.326, P=0.004). Conclusions1. The incidence of colon cancer was associated with the berrant upregulation of AEG-1、β-catenin and LEF-1, so they can provide potential targets for the therapy of colon cancer.2. The expression of AEG-1, β-catenin and LEF-1 is different in lymph node metastasis, distant metastasis and TNM staging, suggesting that their overexpression play an important role in the invasion and metastasis of colon cancer,3.The expression of AEG-1 and β-catenin, LEF in colon cancer show a positive correlation, which speculates that the three might be involved in the development of colon cancer by a link.