| Background and ObjectivesEsophageal cancer is the most common cancer worldwide, and it has a high incidencein Asia. There are two main subtypes of esophageal cancer: squamous cell carcinoma andadenocarcinoma. the esophageal squamous cell carcinomas（ESCC）accounts for majorityof all esophageal cancers worldwide. Esophageal squamous epithelial dysplasia areprecursor lesions to ESCC, ESCC may experience aprogressive process from a normalesophagus, esophageal inflammation, dysplasia and finally, carcinoma. Despite advances inmultimodality therapy, due to later period of diagnosis and poorly efficient treatment, theprognosis of patients with ESCC still keeps poor with a lower average5-year survival rateafter complete surgical resection. Metastasis and recurrence is still the main factorsinfluencing the prognosis of esophageal cancer. Therefore, there is an urgent need forprognostic predictive markers of the biological malignant potential of ESCC.The apical junctional complex present in epithelial and endothelial cell of multicellularorganisms, which is consist of tight junctions (TJs), adherens junctions and desmosomes.Tight junctions are necessary for the seal of the cellular sheets to maintain tissue osmoticpressure. At the same time tight junctions can form a fence which restraints diffusion oflipids and membrane proteins to maintain cell polarity, consequently maintaining thedifferential composition between the basolateral and apical domains. Finally, tightjunctions may also be involved in the regulation of multiple cellular functions, such asproliferation and differentiation. The main characteristic of tumor tissue is the loss ofadhesion, destruction of TJ, cell invasive and the lack of normal differentiationTJs are composed of three main membrane proteins, junctional adhesion molecules,occludin and claudins. It is now has been widely accepted that claudins are critical for thetheir barrier functions and TJ structure. To date,24different Claudins have been cloned. Their expression is often tissue specific, the expression of different claudins have thediverse barrier functions in different endothelial and epithelial tissues. It is worth notingthat the claudin expression becomes malleable. In different environment Claudin expressioncan be changed. There are increasing reports on claudin abnormal expression in varioustypes of tumors and its influence on the progression of the disease. Claudin abnormalexpression will undermine epithelial permeability barrier, make the loss of cell polarity,intercellular adhesion force decreased, leading to a variety of tumor occurrence anddevelopment. At the same time, they also found that Claudin expression was related to themetastasis and prognosis of tumor. There have been few studies on claudin expression inESCC and to demonstrate an association with survival. The prognostic significance ofclaudin expression in ESCC has not yet been elucidated. The aim of the present study wasto examine the clinical significance of claudin-3and claudin-4expression in early stages ofESCC development namely esophageal dysplasia and in ESCC. Claudin-3and claudin-4expression was also correlated with clinicopathological parameters of ESCC patients andwith disease prognosis.Method1. A total of45fresh endoscopic biopsy specimens, including15cases of normalesophageal epithelium,20cases of esophagitis,20cases of dysplasia(8cases of severedysplasia,6cases of moderate dysplasia and6cases of mild dysplasia）were enrolled in thestudy. Biopsy specimens were fixed with formalin and embed with paraffin. Paraffinsections (4μm thick) were routinely stained with hematoxylin and eosin. Histological slideswere estimated blindly and independently by two experienced gastrointestinal pathologists.The paraffin specimens of esophageal squamous carcinoma were acquired from93patientswho underwent radical esophagectomy at Southwest Hospital. In all cases, the complete thepathological and clinical data were obtained for the analysis. This study was approved bythe Bioethical Committee of the southwest hospital, and all patients signed an informedconsent before inclusion.2. Paraffin specimens from93cases of patients with ESCC were made into tissuemicroarray.3. Claudin-3and Claudin-4expressions were analysed in clinical specimens fromhistologically normal esophageal tissues, esophagitis，dysplasia, and ESCC using a specific anti-Claudin-3and Claudin-4antibody by immunohistochemistry (Envision).4. The chi-square test (X2test) statistical method was used to analyze the differenceof Claudin3and4expression in different groups. The Kappa test and the McNemanr testwas used to evaluate the releationship between Claudin3and4. Kaplan-Meier methodanalyzed survival rate, Log-rank test got used to compare survival rate in differentgroups.Differences with a P-value of0.05or less were considered to be statisticallysignificant.Result1. Claudin3proteins mainly located in the cell membrane, partly in the nucleus andcytoplasm. Claudin3expression was found in43.0%(40/93）of ESCC，30%（6/20）ofdysplasia，20%（4/20）of esophagitis，and6.7%(1/15) of normal esophageal epithelium.The positive rate was lowest in normal esophageal epithelium，highest in cancer tissue. Thepositive rate of Claudin3expression in ESCC was significant higher than that in normalesophageal tissue (p<0.05), but no significant difference was found between normalesophageal mucosal tissues and esophagitis or dysplasia (P>0.05).2. Claudin4proteins mainly located in the cell membrane, partly in the nucleus andcytoplasm. Claudin4expression was present in45.2%（42/93）of ESCC，40%（8/20）ofdysplasia,35%（7/20）of esophagitis and33.3%（5/15）of normal esophageal epithelium.No significant difference was found between each group（P>0.05）.3. The expression of claudin3and claudin4in ESCC was associated with patientsurvival and lymphatic metastasis (P<0.05), but not associated with other clinicopathologicfactors（P>0.05）.4. There is no significant difference between the positive rate of Claudin3andClaudin4in ESCC and Claudin3expression is significant correlated to Claudin4expression（K=0.302，P<0.05）.5. Kaplan-Meier survival analysis indicated that the survival rate in patient withoutClaudin3and Claudin4expressions was significantly lower than that in patients withClaudin3and Claudin4expression(P<0.05).ConclusionIn this study, we found that the expression of claudin3was gradually increased innormal esophageal epithelium, esophagitis, hyperplasia and squamous carcinoma tissues. The positive rate of Claudin3expression in ESCC was significant higher than that innormal esophageal tissue (p<0.05), but no significant difference was found between normalesophageal mucosal tissues and esophagitis or dysplasia. Our result suggest that claudin3may be involved in the development of ESCC. But claudin4expression is not associatedwith the development of ESCC. We also found down-regulation of claudin3and4isassociated with lymphatic metastasis in ESCC and they could serve as potential markers forpredicting prognosis of patients with ESCC. |
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