Abstract
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.
Highlights
Fucosylation is one of the most important oligosaccharide modifications in cancer and inflammation [1]
We found that complete loss of fucosylation due to deletion mutation of GMDS gene allowed colon cancer cells to escape from natural killer cell-mediated tumor surveillance through modulation of tumor necrosis factor-related apoptosisinducing ligand (TRAIL) signaling [9], suggesting that a novel metastatic pathway dependent on loss of fucosylation
GMDS Mutation in Colorectal Cancer To examine the frequency of GMDS mutation in original and metastatic colorectal cancers, total RNA was extracted from 81 samples of human original colorectal cancer tissues, 39 samples of metastatic cancer tissues, and adjacent normal colon tissues and was subjected to Reverse Transcriptionpolymerase Chain Reaction (RT-PCR) analysis
Summary
Fucosylation is one of the most important oligosaccharide modifications in cancer and inflammation [1]. Several antibodies that recognize fucosylated glycoproteins or glycolipids in sera of patients with cancer have long been used as tumor markers [5]. We found that complete loss of fucosylation due to deletion mutation of GMDS gene allowed colon cancer cells to escape from natural killer cell-mediated tumor surveillance through modulation of tumor necrosis factor-related apoptosisinducing ligand (TRAIL) signaling [9], suggesting that a novel metastatic pathway dependent on loss of fucosylation. If loss of fucosylation is critical for tumor metastasis during colorectal cancer progression, the frequency of GMDS mutation would likely be increased in metastatic lesions. We investigated the frequency of GMDS mutation in metastatic colorectal cancer tissues such as liver and lymph node
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