Dihydropyrimidine dehydrogenase (DPD) expression is negatively regulated by certain microRNAs in human lung tissues

Takeshi Hirota, Yuko Date, Yu Nishibatake, Hiroshi Takane, Yasushi Fukuoka, Yuuji Taniguchi, Naoto Burioka, Eiji Shimizu, Hiroshige Nakamura, Kenji Otsubo, Ichiro Ieiri

研究成果: ジャーナルへの寄稿記事

39 引用 (Scopus)

抄録

Dihydropyrimidine dehydrogenase (DPD) is important to the antitumor effect of 5-fluorouracil (5-FU). DPD gene (DPYD) expression in tumors is correlated with sensitivity to 5-FU. Because the 5-FU accumulated in cancer cells is also rapidly converted into inactivated metabolites through catabolic pathways mediated by DPD, high DPD activity in cancer cells is an important determinant of the response to 5-FU. DPD activity is highly variable and reduced activity causes a high risk of 5-FU toxicity. Genetic variation in DPYD has been proposed as the main factor responsible for the variation in DPD activity. However, only a small proportion of the activity of DPD can be explained by DPYD mutations. In this study, we found that DPYD is a target of the following microRNAs (miRNA): miR-27a, miR-27b, miR-134, and miR-582-5p. In luciferase assays with HepG2 cells, the overexpression of these miRNAs was associated with significantly decreased reporter activity in a plasmid containing the 3'-UTR of DYPD mRNA. The level of DPD protein in MIAPaca-2 cells was also significantly decreased by the overexpression of these four miRNAs. The results suggest that miR-27a, miR-27b, miR-134, and miR-582-5p post-transcriptionally regulate DPD protein expression. The levels of miRNAs in normal lung tissue and lung tumors were compared; miR-27b and miR-134 levels were significantly lower in the tumors than normal tissue (3.64 ± 4.02 versus 9.75 ± 6.58 and 0.64 ± 0.75 versus 1.48 ± 1.39). DPD protein levels were significantly higher in the tumors. Thus, the decreased expression of miR-27b would be responsible for the high levels of DPD protein. This study is the first to show that miRNAs regulate the DPD protein, and provides new insight into 5-FU-based chemotherapy.

元の言語英語
ページ(範囲)16-23
ページ数8
ジャーナルLung Cancer
77
発行部数1
DOI
出版物ステータス出版済み - 7 1 2012

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Dihydrouracil Dehydrogenase (NADP)
MicroRNAs
Lung
Fluorouracil
Neoplasms
Proteins
Hep G2 Cells
3' Untranslated Regions
Luciferases

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

これを引用

Dihydropyrimidine dehydrogenase (DPD) expression is negatively regulated by certain microRNAs in human lung tissues. / Hirota, Takeshi; Date, Yuko; Nishibatake, Yu; Takane, Hiroshi; Fukuoka, Yasushi; Taniguchi, Yuuji; Burioka, Naoto; Shimizu, Eiji; Nakamura, Hiroshige; Otsubo, Kenji; Ieiri, Ichiro.

:: Lung Cancer, 巻 77, 番号 1, 01.07.2012, p. 16-23.

研究成果: ジャーナルへの寄稿記事

Hirota, T, Date, Y, Nishibatake, Y, Takane, H, Fukuoka, Y, Taniguchi, Y, Burioka, N, Shimizu, E, Nakamura, H, Otsubo, K & Ieiri, I 2012, 'Dihydropyrimidine dehydrogenase (DPD) expression is negatively regulated by certain microRNAs in human lung tissues', Lung Cancer, 巻. 77, 番号 1, pp. 16-23. https://doi.org/10.1016/j.lungcan.2011.12.018
Hirota, Takeshi ; Date, Yuko ; Nishibatake, Yu ; Takane, Hiroshi ; Fukuoka, Yasushi ; Taniguchi, Yuuji ; Burioka, Naoto ; Shimizu, Eiji ; Nakamura, Hiroshige ; Otsubo, Kenji ; Ieiri, Ichiro. / Dihydropyrimidine dehydrogenase (DPD) expression is negatively regulated by certain microRNAs in human lung tissues. :: Lung Cancer. 2012 ; 巻 77, 番号 1. pp. 16-23.
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abstract = "Dihydropyrimidine dehydrogenase (DPD) is important to the antitumor effect of 5-fluorouracil (5-FU). DPD gene (DPYD) expression in tumors is correlated with sensitivity to 5-FU. Because the 5-FU accumulated in cancer cells is also rapidly converted into inactivated metabolites through catabolic pathways mediated by DPD, high DPD activity in cancer cells is an important determinant of the response to 5-FU. DPD activity is highly variable and reduced activity causes a high risk of 5-FU toxicity. Genetic variation in DPYD has been proposed as the main factor responsible for the variation in DPD activity. However, only a small proportion of the activity of DPD can be explained by DPYD mutations. In this study, we found that DPYD is a target of the following microRNAs (miRNA): miR-27a, miR-27b, miR-134, and miR-582-5p. In luciferase assays with HepG2 cells, the overexpression of these miRNAs was associated with significantly decreased reporter activity in a plasmid containing the 3'-UTR of DYPD mRNA. The level of DPD protein in MIAPaca-2 cells was also significantly decreased by the overexpression of these four miRNAs. The results suggest that miR-27a, miR-27b, miR-134, and miR-582-5p post-transcriptionally regulate DPD protein expression. The levels of miRNAs in normal lung tissue and lung tumors were compared; miR-27b and miR-134 levels were significantly lower in the tumors than normal tissue (3.64 ± 4.02 versus 9.75 ± 6.58 and 0.64 ± 0.75 versus 1.48 ± 1.39). DPD protein levels were significantly higher in the tumors. Thus, the decreased expression of miR-27b would be responsible for the high levels of DPD protein. This study is the first to show that miRNAs regulate the DPD protein, and provides new insight into 5-FU-based chemotherapy.",
author = "Takeshi Hirota and Yuko Date and Yu Nishibatake and Hiroshi Takane and Yasushi Fukuoka and Yuuji Taniguchi and Naoto Burioka and Eiji Shimizu and Hiroshige Nakamura and Kenji Otsubo and Ichiro Ieiri",
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AU - Hirota, Takeshi

AU - Date, Yuko

AU - Nishibatake, Yu

AU - Takane, Hiroshi

AU - Fukuoka, Yasushi

AU - Taniguchi, Yuuji

AU - Burioka, Naoto

AU - Shimizu, Eiji

AU - Nakamura, Hiroshige

AU - Otsubo, Kenji

AU - Ieiri, Ichiro

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