Cancer Cell：区分肾癌亚型 有前景的新药靶点

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 Molinie, Stephane Richard, Puay Hoon Tan, Bin Tean Teh, Kyle A. Furge

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-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.

Highlights ：Increased expression of AKR1B10 is a prominent feature of FH null cells ? Fumarate mediates the stabilization of NRF transcription factors ? The KEAP1-NRF axis is deregulated in type 2 papillary renal cell carcinomas ? Complete gene expression profiles of FH null kidney cancers are presented.

Significance ：Type 2 papillary renal cell carcinoma (PRCC2) is an aggressive disease with no effective treatment. Despite the obvious orphological, genetic, and clinical differences, hereditary PRCC2 is thought to share similar pathway deregulation with ts clear-cell counterpart (CCRCC) that arises as a result of SDH or VHL mutation. Furthermore, the robust response seen ith anti-VEGF agents in CCRCC is not reproducible in PRCC2. This represents a distinct knowledge gap in the understanding of PRCC2 biology. We identi?ed deregulation of the KEAP1-NRF2 axis as a feature that distinguishes PRCC2 rom CCRCC, but links both hereditary and sporadic PRCC2. Therefore, our finding provides a more complete understanding of PRCC2 biology and lays the foundation for the development of effective treatment strategies.