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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

345 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)511-523
Number of pages13
JournalCancer cell
Volume20
Issue number4
DOIs
StatePublished - Oct 18 2011

Funding

We thank Sabrina Noyes for administrative support and David Nadziejka for technical editing. We acknowledge the Van Andel Research Foundation, the Singapore Millennium Foundation, and Fondation IGR & INCa (PNES Rein and Centre Expert National Cancers Rares PREDIR) for funding. A.O., K.F., and B.T. designed the study; A.O. performed all experiments, bioinformatics, and data analysis; J.C.W. and D.R. performed IHC staining; D.P. performed microarray experiments; D.W. performed tandem mass spectrometry; and X.J.Y. and M.Z. performed histological evaluation. B.T., Z.Z., M.Z., M.H.T., B.H.W., V.P.T., P.H.T., B.G., V.M., and S.R. provided samples and clinical data. A.O. and K.F. prepared the manuscript. Mass spectrometry and data analysis were performed in the Michigan State University, Proteomic Core Facility.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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