The importance of mitochondrial folate enzymes in human colorectal cancer

Masaaki Miyo, Masamitsu Konno, Hugh Colvin, Naohiro Nishida, Jun Koseki, Koichi Kawamoto, Kenta Tsunekuni, Junichi Nishimura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Yuichiro Doki, Masaki Mori, Hideshi Ishii

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Abstract

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.

Original languageEnglish
Pages (from-to)417-425
Number of pages9
JournalOncology reports
Volume37
Issue number1
DOIs
Publication statusPublished - Jan 2017

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Folic Acid
Colorectal Neoplasms
Survival
Enzymes
Recurrence
Methylenetetrahydrofolate Dehydrogenase (NADP)
Hydroxymethyl and Formyl Transferases
DNA Repair
Serine
Methylation
Carcinogenesis
Carbon
Multivariate Analysis
Nucleotides
aldehyde dehydrogenase 1
Neoplasms
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Miyo, M., Konno, M., Colvin, H., Nishida, N., Koseki, J., Kawamoto, K., ... Ishii, H. (2017). The importance of mitochondrial folate enzymes in human colorectal cancer. Oncology reports, 37(1), 417-425. https://doi.org/10.3892/or.2016.5264

The importance of mitochondrial folate enzymes in human colorectal cancer. / Miyo, Masaaki; Konno, Masamitsu; Colvin, Hugh; Nishida, Naohiro; Koseki, Jun; Kawamoto, Koichi; Tsunekuni, Kenta; Nishimura, Junichi; Hata, Taishi; Takemasa, Ichiro; Mizushima, Tsunekazu; Doki, Yuichiro; Mori, Masaki; Ishii, Hideshi.

In: Oncology reports, Vol. 37, No. 1, 01.2017, p. 417-425.

Research output: Contribution to journalArticle

Miyo, M, Konno, M, Colvin, H, Nishida, N, Koseki, J, Kawamoto, K, Tsunekuni, K, Nishimura, J, Hata, T, Takemasa, I, Mizushima, T, Doki, Y, Mori, M & Ishii, H 2017, 'The importance of mitochondrial folate enzymes in human colorectal cancer', Oncology reports, vol. 37, no. 1, pp. 417-425. https://doi.org/10.3892/or.2016.5264
Miyo M, Konno M, Colvin H, Nishida N, Koseki J, Kawamoto K et al. The importance of mitochondrial folate enzymes in human colorectal cancer. Oncology reports. 2017 Jan;37(1):417-425. https://doi.org/10.3892/or.2016.5264
Miyo, Masaaki ; Konno, Masamitsu ; Colvin, Hugh ; Nishida, Naohiro ; Koseki, Jun ; Kawamoto, Koichi ; Tsunekuni, Kenta ; Nishimura, Junichi ; Hata, Taishi ; Takemasa, Ichiro ; Mizushima, Tsunekazu ; Doki, Yuichiro ; Mori, Masaki ; Ishii, Hideshi. / The importance of mitochondrial folate enzymes in human colorectal cancer. In: Oncology reports. 2017 ; Vol. 37, No. 1. pp. 417-425.
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