The VHL/HIF axis in clear cell renal carcinoma

Shen, Chuan; Kaelin, William G.

doi:10.1016/j.semcancer.2012.06.001

Cited by 329 publications

(337 citation statements)

References 137 publications

(121 reference statements)

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“…Finally, loss of VHL results in the accumulation of HIF-α subunits, leading to activation of the HIF-2 (and possibly HIF-1) transcription factors (25). To determine whether Vhl loss may similarly induce Hif in the mouse, we performed qRT-PCR assays for a panel of Hif-2 and Hif-1 target genes, including VEGF, PAI-1, Glut1, IGFBP3, and PGK1 (26).…”

Section: Vhl Deletion In Kidney Progenitor Cells Causes Delayed Cysticmentioning

confidence: 99%

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis

Wang

Wolff

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

129

107

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Significance Despite the discovery of the von Hippel–Lindau ( VHL ) gene in 1993, and that inactivating germ-line mutations of VHL cause multiple kidney lesions, including clear-cell renal cell carcinoma (ccRCC), Vhl inactivation in the mouse does not lead to ccRCC and a mouse model has been lacking. We discovered that the BRCA1-associated protein-1 ( BAP1 ) two-hit tumor suppressor gene is mutated in ccRCC, and one BAP1 allele is frequently somatically codeleted with VHL in tumors. In the mouse, Vhl and Bap1 are on different chromosomes. We show that SIX homeobox 2 ( Six2 ) -Cre;Vhl F/F ;Bap1 F/ + mice develop premalignant lesions and malignant ccRCC resembling VHL syndrome. More broadly, differences in tumor predisposition across species may result from differences in the location of two-hit tumor suppressor genes across the genome.

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Section: Vhl Deletion In Kidney Progenitor Cells Causes Delayed Cysticmentioning

confidence: 99%

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis

Wang

Wolff

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

129

107

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“…The inactivation of the VHL tumor suppressor protein and the deregulation of VHL/HIF-1a axis are common events in ccRCC [5]. The role of pVHL has been extensively studied [5].…”

Section: Discussionmentioning

confidence: 99%

“…The role of pVHL has been extensively studied [5]. pVHL is a multifunctional protein whose function has been clearly linked to kidney carcinogenesis due to its role in the polyubiquitination process.…”

Section: Discussionmentioning

confidence: 99%

“…pVHL exists in two different isoforms: pVHL30 and pVHL19 [4]. pVHL19 has been shown to contribute to the formation of an ubiquitin ligase (E3) complex (VEC), which controls the proteasomal degradation of several target genes including the hypoxia-inducible factor-1a (HIF-1a) [5]. The ability of pVHL and HIF-1a to bind each other depends upon the cellular oxygen level.…”

Section: Introductionmentioning

confidence: 99%

“…On the contrary, under hypoxic conditions, the non-hydroxylated HIF-1a cannot bind pVHL and is free to translocate into the nucleus. Once in the nucleus, HIF-1a dimerizes with the HIF-1b subunit and trans-activate its target genes [6], which are mainly involved in the resistance to hypoxia, in the glucose uptake and metabolism (Glut1), regulation of extracellular pH (CAIX), angiogenesis (VEGF), erythropoiesis (EPO), and mitogenesis (PDGF-B) [5].…”

Section: Introductionmentioning

confidence: 99%

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VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma

et al. 2014

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Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1a (HIF-1a) expression is regulated by O 2 level. In normal O 2 conditions, VHL binds HIF-1a and allows HIF-1a proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1a interaction is abolished and HIF-1a activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1a gene (HIF-1a) on prognosis in early-stage ccRCC (pT1a, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1a C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1a protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12 % of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1a C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1a protein in the nucleus. Our results highlight the role of VHL/HIF-1a pathway in RCC and support the molecular heterogeneity of earlystage ccRCC. More important, we show the involvement of HIF-1a C1772T SNP in ccRCC progression.

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Secretogranin II impairs tumor growth and angiogenesis by promoting degradation of hypoxia‐inducible factor‐1α in colorectal cancer

et al. 2021

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Distant metastasis is a major cause of death in patients with colorectal cancer (CRC), but the management of advanced and metastatic CRC still remains problematic due to the distinct molecular alterations during tumor progression. Tumor angiogenesis is a key step in tumor growth, invasion, and metastasis. However, the signaling pathways involved in angiogenesis are poorly understood. The results of the present study showed that secretogranin II (SCG2) was significantly downregulated in malignant CRC tissues and higher expression of SCG2 was correlated with longer disease-free survival and overall survival of CRC patients. The results of an animal study showed that ectopic expression of SCG2 significantly inhibited CRC tumor growth by disrupting angiogenesis. Furthermore, the inhibition of expression of vascular endothelial growth factor (VEGF) by SCG2 and rescue of VEGF efficiently blocked SCG2-induced inhibition of angiogenesis. Investigations into the underlying mechanism suggested that SCG2 promoted degradation of hypoxia-inducible factor (HIF)-1α by interacting with the von Hippel-Lindau (VHL) tumor suppressor in CRC cells. Blocking of degradation of HIF-1α efficiently attenuated

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The VHL/HIF axis in clear cell renal carcinoma

Cited by 329 publications

References 137 publications

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis

Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis

VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma

Secretogranin II impairs tumor growth and angiogenesis by promoting degradation of hypoxia‐inducible factor‐1α in colorectal cancer

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