Publication: D-2-hydroxyglutarate dehydrogenase in breast carcinoma as a potent prognostic marker associated with proliferation
Authors
Hayashi, Chiaki ; Takagi, Kiyoshi ; Sato, Ai ; Yamaguchi, Mio ; Minemura, Hiroyuki ; Miki, Yasuhiro ; Harada-Shoji, Narumi ; Miyashita, Minoru ; Sasano, Hironobu ; Suzuki, Takashi
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Publisher
Universidad de Murcia, Departamento de Biologia Celular e Histiologia
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DOI
https://doi.org/10.14670/HH-18-362
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info:eu-repo/semantics/article
Description
Abstract
Background. D-2-hydroxyglutarate
dehydrogenase (D2HGDH) catalyzes D-2-hydroxyglutarate to α-ketoglutarate and is involved in the
regulation of cellular energy and biosynthetic
intermediates. Previously, D2HGDH was reported to
decrease 2-hydroxyglutarate level in breast carcinoma
cells, but no other report has examined D2HGDH in
breast carcinoma, and its significance remains unknown.
Methods. We first immunolocalized D2HGDH in
224 invasive breast carcinomas and evaluated its
clinicopathological significance. We next examined
associations between gene expression of D2HGDH and
α-ketoglutarate-dependent dioxygenases in 23 breast
carcinoma tissues using the gene expression profile data.
Finally, we examined the effects of D2HGDH on the
proliferation in three breast carcinoma cells.
Results. D2HGDH immunoreactivity was detected
in 49% of invasive breast carcinomas, and the
immunohistochemical D2HGDH status was positively
associated with histological grade, HER2 and Ki-67,
while it was inversely associated with estrogen receptor.
Moreover, it was significantly associated with worse
prognosis of the breast cancer patients, and it turned out
to be an independent prognostic factor for both the
disease-free and breast cancer-specific survival in these
patients. Gene expression profile data revealed that
D2HGDH expression was positively associated with the
expression of 6 α-ketoglutarate-dependent dioxygenases
(KDM3A, PLOD1, EGLN2, ALKBH1, ASPH and
ALKBH7). Consequent in vitro experiments
demonstrated that D2HGDH overexpression
significantly increased the cell proliferation activity of
MCF-7, T47D and MDA-MB-231 cells.
Conclusion. These results suggest that D2HGDH
plays an important role in the growth of breast
carcinoma, possibly through regulating functions of αketoglutarate-dependent dioxygenases, and that
D2HGDH status is a potent worse prognostic factor in
breast cancer patients
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Citation
Histology and Histopathology Vol. 36, nº10 (2021)
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