An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma
Aikseng Ooi, Jing-Chii Wong, David Petillo, Douglas Roossien, Victoria Perrier-Trudova, Douglas Whitten, Bernice Wong Hui Min, Min-Han Tan, Zhongfa Zhang, Ximing J Yang, Ming Zhou, Betty Gardie, Vincent Molinié, Stéphane Richard, Puay Hoon Tan, Bin Tean Teh, Kyle A Furge, Aikseng Ooi, Jing-Chii Wong, David Petillo, Douglas Roossien, Victoria Perrier-Trudova, Douglas Whitten, Bernice Wong Hui Min, Min-Han Tan, Zhongfa Zhang, Ximing J Yang, Ming Zhou, Betty Gardie, Vincent Molinié, Stéphane Richard, Puay Hoon Tan, Bin Tean Teh, Kyle A Furge
Abstract
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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Source: PubMed