Abstract
Mutations and epigenetic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) are major causes of clear-cell renal cell carcinoma (ccRCC) that may originate from chronic inflammation. However, the role of VHL loss of function in the development of ccRCC via inflammation remains poorly understood. VHL-mutant cells exhibit metabolic abnormalities that can cause chronic endoplasmic reticulum (ER) stress and unfolded protein response. We hypothesize that unresolved ER stress induces the inflammatory responses observed in ccRCC. ER stress markers including BiP and XBP1s were significantly increased in cultured and primary VHL loss-of-function kidney cells. In epithelial cells, the kinase activity of IRE1α was required for the induction of NF-κB and JNK and for the recruitment of macrophages. IRE1α kinase activity was also important for the development of fibrotic phenotype in conditional Vhlh knockout mice. Our results offer insights into the therapeutic potential against ccRCC development by relieving metabolic stress. Such cancer prevention strategy may be critical for high-risk cohorts such as the familial VHL disease patients. Cancer Res; 77(13); 3406-16. ©2017 AACR.
Highlights
Genomic mutations and epigenetic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene underlie the development of a majority of clear-cell renal cell carcinoma
The results suggest that endoplasmic reticulum (ER) stress in VHL loss-of-function cells can induce macrophage chemotaxis, which is further increased by exacerbating the stress level with tunicamycin
Fibrotic phenotype and defective kidney function of the Vhlh conditional knockout mice are rescued by treatment of APY29
Summary
Genomic mutations and epigenetic inactivation of the VHL tumor suppressor gene underlie the development of a majority of clear-cell renal cell carcinoma (ccRCC; refs. 1, 2). Genomic mutations and epigenetic inactivation of the VHL tumor suppressor gene underlie the development of a majority of clear-cell renal cell carcinoma Its most prominent target is the alpha subunit of the hypoxiainducible factor (HIF-a). HIF is a master transcription factor stabilized in low oxygen tension, which induces a metabolic switch from oxidative phosphorylation to glycolysis [3, 4]. HIF promotes angiogenesis through expression of cytokines such as VEGF [5]. In VHL-mutant ccRCC cells, HIF function is activated even in normal oxygen conditions [6, 7], exhibiting heightened pseudohypoxic responses. CcRCC is an excellent model for studying tumor metabolism and the interaction between tumor cells and the microenvironment [8]
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