Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Histol Histopathol. 2021 Oct;36(10):1053-1062. doi: 10.14670/HH-18-362. Epub 2021 Jul 23.
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.
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.
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.
These results suggest that D2HGDH plays an important role in the growth of breast carcinoma, possibly through regulating functions of α-ketoglutarate-dependent dioxygenases, and that D2HGDH status is a potent worse prognostic factor in breast cancer patients.
D-2-羟戊二酸脱氢酶（D2HGDH）催化 D-2-羟戊二酸转化为α-酮戊二酸，参与细胞能量和生物合成中间产物的调节。先前有报道称，D2HGDH 可降低乳腺癌细胞中的 2-羟戊二酸水平，但尚无其他研究检测过乳腺癌中的 D2HGDH，其意义尚不清楚。
我们首先在 224 例浸润性乳腺癌中免疫定位了 D2HGDH，并评估了其临床病理意义。我们接下来使用基因表达谱数据检查了 23 例乳腺癌组织中 D2HGDH 基因表达与 α-酮戊二酸依赖性双加氧酶之间的关联。最后，我们在三种乳腺癌细胞中检查了 D2HGDH 对增殖的影响。
49%的浸润性乳腺癌中检测到 D2HGDH 免疫反应性，免疫组化 D2HGDH 状态与组织学分级、HER2 和 Ki-67 呈正相关，与雌激素受体呈负相关。此外，它与乳腺癌患者的预后显著相关，并且是这些患者无病生存率和乳腺癌特异性生存率的独立预后因素。基因表达谱数据显示，D2HGDH 表达与 6 种 α-酮戊二酸依赖性双加氧酶（KDM3A、PLOD1、EGLN2、ALKBH1、ASPH 和 ALKBH7）的表达呈正相关。随后的体外实验表明，D2HGDH 过表达显著增加了 MCF-7、T47D 和 MDA-MB-231 细胞的增殖活性。
这些结果表明，D2HGDH 在乳腺癌的生长中发挥重要作用，可能通过调节 α-酮戊二酸依赖性双加氧酶的功能，并且 D2HGDH 状态是乳腺癌患者强有力的预后不良因素。
