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，肿瘤细胞上的碳水化合物配体成分sialyl Lewis x （sLex）和sialyl Lewis a （sLea）一直被认为是人类癌症发生和进展的标志物。最近的数据显示炎症在结直肠癌发病机制中的重要作用，表明选择素配体作为潜在的翻译靶点。虽然相应的糖基转移酶在恶性细胞和肿瘤标本中的表达很复杂，但sLex和sLea的合成似乎主要由人类α(1,3)聚焦转移酶基因家族控制。其中两个基因在结直肠癌中高表达：FUT3和FUT6。我们的研究表明，通过反义FUT3序列抑制CRC细胞中sLex/sLea的表达可显著减少nu/nu小鼠的CRC转移。此外，FUT6的反义抑制——在结直肠癌中经常与FUT3共表达，并由炎症细胞因子诱导——导致体外和体内癌细胞增殖减少。FUT3和FUT6的突变在不同的人群中已经被描述过，但没有信息可以确定这些无效表型对CRC的发生和/或进展的影响。同样，由于缺乏足够的人类数据集和样本，转录物水平上的表达也受到限制。在过去的几年里，在UNC， SPORE研究人员帮助收集了大量的CRC患者数据集和适当的标本。我们建议：1。识别

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.