Clinical Significance Of L1, β-catenin And E-cadherin Expression In Colorectal Cancer

Introduction:Colorectal cancer is one of the most common tumors in China,with increasing morbidity.The two major features of malignant tumors are infiltration and metastasis, which are the major threatens for post-operative patients.Elucidating the biological events which influence the prognosis,and predicting the infiltrated and metastatic tendency of colorectal cancer,will provide guidance for the doctors,helping them to use more effective comprehensive theraputic strategies.At the same time,studies of the molecular mechanisms of the infiltration and metastasis can provide theoretical basis of gene therapy for the colorectal cancer.Infiltration of tumors is a process of interaction between tumor cells and extracellular matrix.There are three steps which are cell adhesion,matrix degradation and cell migration.Disruption of cell-cell adhesion has been considered as the first step of the complicated process of tumor metastasis.L1 is one of glycoproteinⅠof the immunoglobulin superfamily that play an important role in the development of the nervous system by regulation of cell interactions,including neuronal migration,neurite outgrowth and fasciculation,and synaptic plasticity.L1 is expressed in a variety of tumor cells of neuranal,mesothelial and epithelial origin,such as neuroblastomas,melanomas,lymphomas,small cell lung cancer,colon and breast cancers,and plays a key role in tumor metastasis.β-catenin(β-cat),a multiple-function protein interacting with dozens of different protein in cells,is a product of a new oncogene,and belongs to the cyclic-link protein family.As an important signal transducer and interecellular adhesion molecular,β-cat has become a new hot issue of research.β-cat plays an important role in Wnt signaling pathway,at the same time,is a key intracellular component of E-cad/cat complex involved in intercellular adhesion.It possesses the capability of binding with manifold proteins,which was closely related to cell proliferation,cell differentiation, tumorigenesis,tumor invasion and metastasis.As one of the cell adhesion molecules,E-cadherin(E-cad) is a transmembrane glycoprotein that is responsible for calcium-dependent intercellular adhesion by homophilic interaction.It is expressed in the epithelium,mesothelium and placenta where it maintains the epithelial structure and polarity.It has been demonstrated that the E-cad expression is lower in a lot of human malignant tumors,and the lower E-cad expression seemed to be closely related to the infiltration and metastasis or prognosis of malignant tumors.In the present study,we investigated the expression of L1,β-cat and E-cad,in colorectal cancer tissues by using immunohistochemical method(EnVision) to evaluate the clinical values of L1,β-cat and E-cad,in predicting the invasive,metastatic potential and progonsis of colorectal cancer,and to provide useful molecular biological indicators for comprehensive therapies to colorectal cancer.142 patients with colorectal cancer who underwent surgical resection at Zhejiang Provincial People's Hospital from January 1998 to December 2001 were admitted.The control group included 30 normal colorectal mucosa and 30 colorectal adenomas.The classification was according to Dukes.All the specimens were fixed in 10%formalin and embedded in paraffin.Consecutive section from each specimen were stained with hemotoxylin-eosin for evaluating parameters,and with immunohistochemical technology(EnVision) for evaluating the expression of L1,β-cat and E-cad.SPSS-14 program was used for statistical calculation.The correlation between grading of L1,β-cat and E-cad,expression and the various clinicohistologic findings was analyzed by chi-square test or Fishers exact probability test.The univariate survival analysis was based on the life table method with statistics by Kaplan-Meier,multivariate survival analysis was based on Cox regression analysis.Correlation was analyzed by Spearman.P values＜0.05 were considered significant.In the normal colorectal mucosa epithelial,L1 expressed as negative with 100% (30/30).For colorectal adenomas samples,100%(30/30) expressed as negtive.For colorectal cancer,69.01%(98/142) expressed as negtive,30.99%(44/142) as positive.It indicates that the expression of L1 in colorectal cancer tissues is higher than normal colorectal mucosa and colorectal adenomas.There was significant defference between the normal epithelium and the cancer group(p＜0.05).Of the 30 normal colorectal mucosa epithelial samples,100%(30/30) expressedβ-cat as positive.For colorectal adenomas samples,30%(9/30) expressed as negtive, 70%(21/30) as positive.For colorectal cancer,with 71.13%(101/142) expressed as negtive,28.87%(41/142) as positive.This result implies thatβ-cat is lower expressed in colorectal cancer than in normal colorectal mucosa and in colorectal adenomas.There was significant defference among normal epithelium,adenamas and cancer group each other(p＜0.05).Of the 30 normal colorectal mucosa epithelial samples expressed E-cad,with 100%(30/30) expressed as positive.For colorectal adenomas,with 30%(9/30) expressed as negative,70%(21/30) as positive.For colorectal cancer,with 68.31% (97/142) expressed as negative,31.69%(45/142) as positive.It indicates:expressed E-cad,colorectal cancer is lower than normal colorectal mucosa and colorectal adenomas.There was significant defference among normal epithelium,adenamas and cancer group each other(p＜0.05).The expression of L1,β-cat and E-cad significantly correlated with differentiation, invasion depth,veins,lymphatic,lymphnode metastasis,and Dukes classification.The 1-,3- and 5-year survival rate of the patients expressed L1 as positive,E-cad,β-cat as negative are lower than the patients expressed L1 as negative,E-cad,β-cat as positive.The results of multivariate survival analysis demonstrated that the information from the Dukes classification,as well as the expression level of L1 could predict patient survival. In normal colorectal mucosa,the expression of L1 is negative.the expression of E-cad orβ-cat is positive,however,In Colorectal cancer,the expression of L1 is increase obviously.The expression of L1,β-cat and E-cad significantly correlated with the infiltration,metastasis and prognosis of colorectal cancer.The strong staining intensity of L1 and weak staining intensity of E-cad orβ-cat indicates advanced cancer and poorer prognosis.The expression of E-cad has positive correlation with that ofβ-cat;but the expression of E-cad,β-cat has negative correlation with L1 respectively.Both the expression of L1 and Dukes classification is an independent prognostic predictor in colorectal cancer patients.L1 and E-cad are cell adhesion molecules,andβ-cat is one of the catenins related with adhesion mechanism.The relationship between L1 and human colon carcinoma has not been reported.The research about the relationship between the expression of E-cad orβ-cat and colon carcinoma infiltrates,metastasis and prognosis are reported in very few literature.Thus our research focus on the expression of L1,E-cad andβ-cat in colorectal cancers,which may serve as the clinical guidance for the comprehensive therapies in the future.