Journal
ONCOLOGY REPORTS
Volume 37, Issue 1, Pages 417-425Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/or.2016.5264
Keywords
serine hydroxymethyl transferase; methylenetetrahydrofolate dehydrogenase; aldehyde dehydrogenase 1 family member L2; colorectal cancer; folate
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Funding
- Ministry of Education, Culture, Sports, Science and Technology
- Third Comprehensive 10-year Strategy for Cancer Control, Ministry of Health, Labor and Welfare
- Kobayashi Cancer Research Foundation
- Princess Takamatsu Cancer Research Fund, Japan
- National Institute of Biomedical Innovation
- Osaka University Drug Discovery Funds
- Taiho Pharmaceutical Co., Ltd.
- Chugai Co., Ltd.
- Yakult Honsha Co., Ltd.
- Merck Co., Ltd.
- Takeda Science Foundation
- Takeda Medical Research Foundation
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Folate plays a pivotal role in the one-carbon metabolism needed for methylation reactions, nucleotide synthesis, and DNA repair. Although folate metabolism was recently shown to be associated with carcinogenesis in some solid tumors, the importance of folate metabolism in colorectal cancer remains unclear. In the present investigation we found that expression of three mitochondrial folate metabolic enzymes, serine hydroxymethyl transferase (SHMT2), methylenetetrahydrofolate dehydrogenase (MTHFD2) and aldehyde dehydrogenase 1 family member L2 (ALDH1L2), were upregulated in human colorectal tumor tissues compared to normal tissues. Colorectal cancer tissue samples were obtained from 117 consecutive patients. We evaluated the expression of the enzymes with immunohistochemical analysis and determined their relevance to clinicopathological characteristics and prognosis. Rates of recurrence-free survival (RFS) and overall survival (OS) in patients with high expression of SHMT2, MTHFD2 and ALDH1L2 tended to be lower than in patients with low expression of SHMT2, MTHFD2 and ALDH1L2 (P=0.446 and P=0.337, P=0.099 and P=0.064, P=0.178 and P=0.257, respectively). Notably, the combined high expression of SHMT2, MTHFD2 and ALDH1L2 (triple high) was more highly associated with poor prognosis than the individual expression levels (RFS; P=0.004 and OS; P=0.037). A multivariate analysis showed that triple high expression was independently associated with RFS (P=0.017). These findings suggested that mitochondrial folate metabolic enzymes could provide a potential therapeutic strategy for treating colorectal cancer.
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