Regulation of Wnt signaling pathway by galectin-3 in hepato-biliary-pancreatic cancer : Special reference to mutation of galectin-3

半乳糖凝集素-3（Galectin-3，gal-3）是一种多功能蛋白，与β-连环蛋白一样，以磷酸化依赖的方式穿梭于细胞核和胞浆之间，是肿瘤转移的重要调节因子。我们在此报告，β-连环蛋白刺激细胞周期蛋白D1和c-myc的表达是半乳糖醛酸-3依赖性的。Gal-3与β-catenin/Tcf复合物结合，与β-catenin共定位于细胞核中，并诱导Tcf-4的转录活性，如TOP/FOPFLASH报告系统所确定的。我们已经鉴定了β-连环蛋白gal-3结合序列，其分别位于蛋白质的NH 2和COOH末端，包括氨基酸残基1至131和143至250。这些结果表明gal-3是一种新的β-catenin结合伴侣，参与Wnt/β-catenin信号通路的调控，人gal-3序列的分析显示其结构与β-catenin相似，因为它也含有糖原合成酶激酶-3 β（GSK-3 β）的共有序列（S92 XXXS 96 ...更多信息 ）磷酸化并可作为其底物。此外，Axin是Wnt的一种调节蛋白，与β-连环蛋白形成复合物，也使用与此处通过缺失突变体分析鉴定的相同序列基序结合半乳糖醛酸-3。本研究通过免疫组织化学方法检测了115例胃癌患者中gal-3和Ki-67的表达，结果表明gal-3是Wnt/β-catenin信号通路中的关键调节因子，并强调了gal-3和β-catenin.Gal-3和Ki-67的功能相似。PCR-单链构象多态性（SSCP）-序列分析及gal-3 mRNA水平检测。本研究表明，gal-3表达与淋巴结状态、淋巴浸润、病理分期和组织学参数有关。另一方面，gal-3表达与Ki-67表达无相关性。gal-3表达降低与预后不良显著相关，多因素分析显示gal-3表达是独立的预后因素。PCR-SSCP-测序结果显示，gal-3基因存在2个单核苷酸多态性（SNP），但均未发现突变。gal-3表达降低与胃癌的淋巴结转移、进展期和分化程度有关。Gal-3的表达可能是胃癌的一个有用的预后因素。免疫组化方法检测了108例大肠癌标本中Galectin-3、β-catenin和Ki-67的表达。将galectin-3的表达分为肿瘤表面和浸润前沿，并从统计学角度考虑其与临床病理因素的关系。当半乳糖凝集素-3在肿瘤侵袭性前沿的表达低于其表面时，存在显著的肝转移（p = 0.04）。β-连环蛋白在肿瘤表面的表达与肝转移和肿瘤分期之间也存在显著相关性（分别为p=0.03，p=0.04）。提示半乳糖凝集素-3表达降低与结直肠癌患者的肿瘤侵袭、转移和增殖有关。少

Galectin-3 (gal-3), a pleiotrophic protein, is an important regulator of tumor metastasis, which like beta-catenin shuttles between the nucleus and the cytosol in a phosphorylation-dependent manner. We report herein that beta-catenin stimulation of cyclin D1 and c-myc expression is gal-3 dependent. Gal-3 binds to beta-catenin/Tcf complex, colocalizes with beta-catenin in the nucleus, and induces the transcriptional activity of Tcf-4 as determined by the TOP/FOPFLASH reporter system. We have identified the beta-catenin gal-3-binding sequences, which are in the NH2 and COOH termini of the proteins encompassing amino acid residues 1 to 131 and 143 to 250, respectively. These data indicate that gal-3 is a novel binding partner for beta-catenin involved in the regulation of Wnt/beta-catenin signaling pathway.Analysis of the human gal-3 sequence reveled a structural similarity to beta-catenin as it also contains the consensus sequence (S92XXXS96) for glycogen synthase kinase-3beta (GSK-3beta … More ) phosphorylation and can serve as its substrate. In addition, Axin, a regulator protein of Wnt that complexes with beta-catenin, also binds gal-3 using the same sequence motif identified here by a deletion mutant analysis. The data presented here give credence to the suggestion that gal-3 is a key regulator in the Wnt/beta-catenin signaling pathway and highlight the functional similarities between gal-3 and beta-catenin.Gal-3 and Ki-67 expressions were assessed by immunohistochemistry in 115 patients with gastric cancer. PCR-single strand conformation polymorphism (SSCP)-sequence analysis and the levels of gal-3 mRNA were also examined. The present study demonstrated that gal-3 expression was correlated with nodal status, lymphatic inivasion, pathological stage and histological parameters. On the other hand, gal-3 expression did not correlate with the expression of Ki-67. Reduced expression of gal-3 was significantly associated with a poor prognosis and multivariate analysis showed that gal-3 expression was an independent prognostic factor. On PCR-SSCP-sequence analysis, 2 single nucleotide polymorphisms (SNPs) were detected in the gal-3 gene, but none showed mutations. Reduced gal-3 expression was associated with lymph node metastasis, advanced stage and tumor differentiation in gastric cancer. Gal-3 expression could be a useful prognostic factor in gastric cancer.Immunohistochemical assessment of galectin-3, beta-catenin and Ki-67 expression was performed on samples from 108 patients with colorectal cancer. The expression of galectin-3 was classified at the tumor surface and the invasive front, and its relationship with clinicopathological factors was considered from a statistical viewpoint. There was significant liver metastasis when the expression of galectin-3 was lower at the invasive front of a tumor compared to its surface (p = 0.04). There were also significant correlations between beta-catenin expression at the tumor surface and liver metastasis and tumor stage (p=0.03, p=0.04 respectively). The reduction of galectin-3 expression in tumor invasion, metastasis and proliferation in patients with colorectal cancer is suggested. Less