An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma
An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma
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DOI：
10.1016/j.ccr.2011.08.024
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发表时间：
2011-10-18
期刊：
影响因子：
50.3
通讯作者：
Furge, Kyle A.
中科院分区：
文献类型：
--
作者：
Ooi, Aikseng;Wong, Jing-Chii;Furge, Kyle A.
富马酸水合酶（FH）突变导致遗传性2型乳头状肾细胞癌（PRCC 2）。FH突变的主要影响是富马酸盐蓄积。当前模式假定富马酸盐蓄积的主要后果是HIF-α稳定。巧合的是，FH突变在其相关的肿瘤类型中不同于其他HIF-α稳定突变，如VHL和SDH突变。我们发现富马酸盐可以直接上调抗氧化反应元件（ARE）控制的基因。我们证明了醛酮还原酶家族1成员B10（AKR 1B 10）是ARE控制的基因，并在FH敲低以及FH空细胞系中上调。AKR 1B 10过表达也是遗传性和散发性PRCC 2的突出特征。这种表型更好地解释了遗传性和散发性PRCC 2之间的相似性。
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-alpha stabilization. Paradoxically, FH mutation differs from other HIF-alpha 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.