Altered Expressions Of E-cadherin And Wnt2 In Gastric Cancers And Their Relevance To Intracellular Distribution Of β-catenin And Tumor Progression

Background and Objective Gastric cancer (GC) is one of the commonest malignancies and themajor cause of cancer-related deaths in China because of the later diagnosisand its strong tendency of local invasiveness and distal metastasis. Multiplegenetic factors are involved in the processes of invasion and metastasis ofgastric cancer but the mechanisms of their differential expression and,especially, their coordinating interaction(s) are still under investigation. Ithas been found that alterations of E-cadherin and β-catenin are correlatedwith the formation and progression of GC. Reduction or loss of E-cadherinexpression has been regarded as a risk factor of cell dedifferentiation andan unfavorable parameter of patient's prognosis. Wnt genes also participatein gastrocarcinogenesis and the up-regulated Wnt2 and Wnt5A have beenobserved in primary gastric cancer. The progressive loss of E-cadherin andgain of Wnt2 expression may influence intracellular distribution ofβ-catenin. β-catenin, when translocating into nucleus, can interact withT-cell factors (TCFs) and induces the transcriptions of a series of targetgenes including some metastasis-related ones such as CD44 and MMPs.Therefore, the patterns of β-catenin distribution are associated with theaggressive behaviors of cancer cells. Apparently, the biological functions ofβ-catenin are double-dealing which are largely determined by the statusesof Wnt and E-cadherin expression. However, the investigations concerningthe functional link(s) of β-catenin with E-cadherin or Wnt have beenperformed separately in gastric cancers. The current study is thus aimed tofigure out potential cross-talk of Wnt and E-cadherin in determining thefate of β-catenin and the correlation with tumor progression. Materials and Methods The surgical specimens were selected from the gastric tissue bank ofCancer Institute, Dalian Medical University. Human gastric cancer celllines AGS and HGC-27 were ordered from American Type CultureCollection (ATCC, USA), and MGC803 and BGC823 were kindlyprovided by Beijing Institute for Cancer Research, Peking University. Thedifferent gastric tissues were classified histologically as relatively normalmucosa, premalignant, and gastric cancer tissues(intestinal type and diffusetype). By the methods of frozen tissue array-based immunohistochemicalstaining, Western blotting and RT-PCR, a paralleled study was conducted tocheck the expression or distribution of E-cadherin, Wnt2, β-catenin indifferent gastric tissues and four human gastric cancer cell lines. TheKruskal-Wallis test or Mann-Whitney test and Spearman correlation testwere used in our present work. Results 1. Membranous E-cadherin was decreased distinctively in gastriccancer samples, especially in diffuse gastric cancers. Wnt2 up-expressionand cytosolic/nuclear accumulations of β-catenin appeared in most gastriccancers irrespective to their morphological phenotypes. 2. In a case of chronic gastritis without membranous E-cadherinlabeling, Wnt2 was invisible and β-catenin was negative on the membraneand unobvious in the nucleus but positive in the cytoplasm. 3. Statistical evaluation revealed a close association of reducedmembranous E-cadherin staining with lymph node metastases(p<0.05). Onthe other hand, no difference could be found between T1,2 and T3,4 groups interms of the density of the membranous E-cadherin labeling. In parallel,increased Wnt2 expression and altered β-catenin distribution could befound in T3,4 and LN+ GC groups(p<0.05). 4. Membranous E-cadherin and its β-catenin partner appearedconcurrently in gastric tissues irrespective to their morphologicaldifferences(r = 0.698, p<0.01). Meanwhile, the cells with reducedmembranous E-cadherin exhibited cytosolic accumulation and nucleartranslocalization of β-catenin(r = –0.398 and r = –0.353 respectively,p<0.01). Furthermore, a significant correlation was found betweenincreased Wnt2 and the loss of membranous E-cadherin(r = – 0.478,p<0.001). 5. The transcripts of β-catenin and Wnt2 were detected at variablelevels and E-cad...