Author/Authors :
Ooi، نويسنده , , Aikseng and Wong، نويسنده , , Jing-Chii and Petillo، نويسنده , , David and Roossien، نويسنده , , Douglas and Perrier-Trudova، نويسنده , , Victoria and Whitten، نويسنده , , Douglas and Min، نويسنده , , Bernice Wong Hui and Tan، نويسنده , , Min-Han and Zhang، نويسنده , , Zhongfa and Yang، نويسنده , , Ximing J. and Zhou، نويسنده , , Ming and Gardie، نويسنده , , Betty and Molinié، نويسنده , , Vincent J. Richard، نويسنده , , Stéphane and Tan، نويسنده , , Puay Hoon and Teh، نويسنده , , Bin Tean and Furge، نويسنده , , Kyle A.، نويسنده ,
Abstract :
Summary
te 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.
