Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Cancer Cell. 2011 Oct 18;20(4):511-23. doi: 10.1016/j.ccr.2011.08.024.
Fumarate hydratase (FH) mutation causes hereditary type 2 papillary renal cell carcinoma (PRCC2). The main effect of FH mutation is fumarate accumulation. The current paradigm posits that the main consequence of fumarate accumulation is HIF-α stabilization. Paradoxically, FH mutation differs from other HIF-α stabilizing mutations, such as VHL and SDH mutations, in its associated tumor types. We identified that fumarate can directly up-regulate antioxidant response element (ARE)-controlled genes. We demonstrated that aldo-keto reductase family 1 member B10 (AKR1B10) is an ARE-controlled gene and is up-regulated upon FH knockdown as well as in FH null cell lines. AKR1B10 overexpression is also a prominent feature in both hereditary and sporadic PRCC2. This phenotype better explains the similarities between hereditary and sporadic PRCC2.
延胡索酸水合酶（FH）突变导致遗传性 2 型乳头状肾细胞癌（PRCC2）。FH 突变的主要作用是积累富马酸。目前的范式假设，富马酸积累的主要后果是 HIF-α 稳定。矛盾的是，FH 突变与其相关的肿瘤类型不同于其他 HIF-α 稳定突变，如 VHL 和 SDH 突变。我们发现富马酸可以直接上调抗氧化反应元件（ARE）控制的基因。我们证明醛酮还原酶家族 1 成员 B10（AKR1B10）是一个 ARE 控制的基因，并在 FH 敲低以及 FH 缺失细胞系中上调。AKR1B10 的过表达也是遗传性和散发性 PRCC2 的一个显著特征。这种表型更好地解释了遗传性和散发性 PRCC2 之间的相似性。
