DETERMINATION OF THE ROLE OF FUCOSYLTRANSFERASES IN COLORECTAL CANCER INTITIATION

选择素介导的细胞粘附与结直肠癌（CRC）的转移有关，肿瘤细胞上的糖配体组分sialyl刘易斯x（sLex）和sialyl刘易斯a（sLea）一直被认为是人类肿瘤发生和发展的标志物。最近的数据显示炎症在CRC发病机制中的重要作用，选择素配体是潜在的翻译靶点。虽然相应的糖基转移酶的表达是复杂的恶性细胞和肿瘤标本，sLex和sLea的合成似乎在很大程度上控制的人α（1，3）岩藻糖基转移酶基因家族。其中两个基因在CRC中高度表达：FUT 3和FUT 6。我们的小组已经表明，通过反义FUT 3序列抑制CRC细胞中的sLex/sLea表达导致nu/nu小鼠中CRC转移显著减少。此外，FUT 6的反义抑制-其通常与CRC中的FUT 3共表达，并且可被炎性细胞因子诱导-导致体外和体内癌增殖降低。FUT 3和FUT 6突变已在不同人群中进行了描述，但没有信息可用于确定这些无效表型对CRC发生和/或进展的影响（如果有的话）。类似地，由于缺乏足够的人类数据集和样品，转录水平的表达受到限制。在过去的几年里，SPORE研究人员帮助收集了大量CRC患者数据集和适当的标本。我们建议：1.识别 与息肉和/或CRC发展相关的FUT 3和/或FUT 6突变，并检查与使用非甾体抗炎药（NSAID）和其他临床变量的潜在相互作用; 2.检查息肉和CRC病变在不同进展阶段的FUT转录水平;和3.联合收割机FUT反义寡核苷酸与NSAIDs联合用于体外和nu/nu小鼠模型中CRC的实验治疗。我们的长期目标是随着我们对选择素配体功能的了解的增长，将这些药物的临床前使用扩展到适当的患者人群。

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.