Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan.
PLoS One. 2013 Jul 29;8(7):e70298. doi: 10.1371/journal.pone.0070298. Print 2013.
Fucosylation is a crucial oligosaccharide modification in cancer. The known function of fucosylation in cancer is to mediate metastasis through selectin ligand-dependent processes. Previously, we found complete loss of fucosylation in the colon cancer cell line HCT116 due to a mutation in the GDP-fucose synthetic enzyme, GDP-mannose-4,6-dehydratase (GMDS). Loss of fucosylation led to escape of cancer cells from tumor immune surveillance followed by tumor progression and metastasis, suggesting a novel function of fucosylation in tumor progression pathway. In the present study, we investigated the frequency of GMDS mutation in a number of clinical colorectal cancer tissue samples: 81 samples of primary colorectal cancer tissue and 39 samples of metastatic lesion including liver and lymph node. Four types of deletion mutation in GMDS were identified in original cancer tissues as well as metastatic lesions. The frequency of GMDS mutation was slightly higher in metastatic lesions (12.8%, 5/39 samples) than in original cancer tissues (8.6%, 7/81 samples). No mutation of the GMDS gene was observed in normal colon tissues surrounding cancer tissues, suggesting that the mutation is somatic rather than in the germline. Immunohistochemical analysis revealed complete loss of fucosylation in three cases of cancer tissue. All three cases had GMDS mutation. In one of three cases, loss of fucosylation was observed in only metastatic lesion, but not its original colon cancer tissue. These data demonstrate involvement of GMDS mutation in the progression of colorectal cancer.
岩藻糖基化是癌症中一种重要的寡糖修饰。岩藻糖基化在癌症中的已知功能是通过选择素配体依赖的过程来介导转移。先前，我们发现由于 GDP-岩藻糖合成酶 GDP-甘露糖-4,6-脱水酶 (GMDS) 的突变，结肠癌细胞系 HCT116 中完全丧失了岩藻糖基化。岩藻糖基化的缺失导致癌细胞逃避肿瘤免疫监视，随后肿瘤进展和转移，这表明岩藻糖基化在肿瘤进展途径中具有新的功能。在本研究中，我们调查了 GMDS 突变在许多临床结直肠癌组织样本中的频率：81 份原发性结直肠癌组织样本和 39 份包括肝和淋巴结的转移病灶样本。在原始癌症组织和转移病灶中鉴定出 GMDS 的四种缺失突变类型。GMDS 突变的频率在转移病灶中略高于原始癌症组织（12.8%，5/39 样本）（8.6%，7/81 样本）。在癌症组织周围的正常结肠组织中未观察到 GMDS 基因的突变，这表明突变是体细胞突变而不是种系突变。免疫组织化学分析显示，在三种癌症组织中有三种完全丧失了岩藻糖基化。这三种情况都有 GMDS 突变。在三种情况中的一种中，仅在转移病灶中观察到岩藻糖基化缺失，而其原始结肠癌组织中没有。这些数据表明 GMDS 突变参与了结直肠癌的进展。
