DETERMINATION OF THE ROLE OF FUCOSYLTRANSFERASES IN COLORECTAL CANCER INTITIATION

选择素介导的细胞黏附与结直肠癌的转移密切相关，肿瘤细胞表面的糖类配体sialyl Lewis x(Slex)和sialyl Lewis a(SleA)一直被认为是人类肿瘤发生发展的标志物。最近的数据显示炎症在结直肠癌的发病机制中扮演着重要的角色，这表明选择素配体是潜在的翻译靶点。尽管相应的糖基转移酶在恶性肿瘤细胞和肿瘤标本中的表达是复杂的，但SLeX和SleA的合成似乎在很大程度上受人类α(1，3)岩藻糖基转移酶基因家族的控制。其中两个基因在结直肠癌中高表达：FUT3和FUT6。我们的团队已经证明，通过反义FUT3序列抑制结直肠癌细胞中SLeX/SleA的表达，可以显著减少nu/nu小鼠的结直肠癌转移。此外，对FUT6的反义抑制--它经常与FUT3在结直肠癌中共表达，并可被炎性细胞因子诱导--导致体内和体外的肿瘤增殖减少。FUT3和FUT6的突变在不同的人群中已经被描述，但还没有信息可以确定这些无效表型对结直肠癌的发生和/或进展的影响(如果有的话)(S)。同样，由于缺乏足够的人类数据集和样本，文字记录一级的表达也受到限制。在过去的几年里，在北卡罗来纳大学，孢子调查人员帮助组装了具有适当标本的大型CRC患者数据集。我们建议：1.确定 FUT3和/或FUT6突变与息肉和/或结直肠癌的发展相关，并检查与使用非类固醇抗炎药(NSAIDs)和其他临床变量的潜在相互作用；2.检测不同进展阶段息肉和结直肠癌皮损中FUT的转录水平；以及3.将FUT反义寡核苷酸与NSAIDs结合用于体外和nu/nu小鼠模型的实验性治疗结直肠癌。我们的长期目标是随着我们对选择素配体功能的理解的加深，将这些药物的临床前使用扩大到适当的患者群体。

Selectin-mediated cell adhesion has been implicated in the metastasis of colorectal carcinoma (CRC), and the carbohydrate ligand components sialyl Lewis x (sLex) and sialyl Lewis a (sLea) on tumor cells have long been considered markers for development and progression of human carcinoma. Recent data showing important roles for inflammation in CRC pathogenesis point to selectin ligands as potential translational targets. Although corresponding glycosyltransferase expression is complex in malignant cells and tumor specimens, sLex and sLea synthesis appears to be largely controlled by the human alpha(1,3)fucosyltransferase gene families. Two of these genes are highly expressed in CRC: FUT3 and FUT6. Our group has shown that inhibition of sLex/sLea expression in CRC cells by antisense FUT3 sequences results in markedly reduced CRC metastases in nu/nu mice. Furthermore, antisense inhibition of FUT6-- which is often co-expressed with FUT3 in CRC and is inducible with inflammatory cytokines-- results in decreased carcinoma proliferation invitro and in vivo. Mutations in FUT3 and FUT6 have been described in diverse human populations, but no information has been available to determine the effect(s), if any, of these null phenotypes on development and/or progression of CRC. Similarly, expression at the transcript level has been limited by lack of adequate human data sets and samples. Over the past several years at UNC, SPORE investigators have helped assemble large CRC patient data sets with appropriate specimens. We propose to: 1. Identify FUT3 and/or FUT6 mutations associated with polyp and/or CRC development and examine potential interactions with use of non-steroidal anti-inflammatory drugs (NSAIDs) and other clinical variables; 2. Examine FUT transcript levels in polyps and CRC lesions at various stages of progression; and 3. Combine FUT antisense oligodeoxynucleotides with NSAIDs for experimental therapy of CRC in vitro and in nu/nu mice models. Our long term goal is extend the pre-clinical use of these agents to appropriate patient populations as our understanding of selectin ligand function grows.