文摘
Summary
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-¦Á stabilization. Paradoxically, FH mutation differs from other HIF-¦Á 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)¨Ccontrolled 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.