Loss of HNF1? function in human renal cell carcinoma: Frequent mutations in theVHL gene but not theHNF1? gene

Abstract

Human renal cell carcinoma (RCC) is a common malignant disease of the kidney characterized by dedifferentiation of renal epithelial cells. Our previous experiments showed that most RCCs have a loss of function of the tissue-specific transcription factor hepatocyte nuclear factor (HNF) 1alpha. Detailed analyses of the 10 exons encoding HNF1alpha in 32 human RCCs by single-strand conformation polymorphism analysis and direct DNA sequencing revealed no tumor-associated mutation, whereas with the same probes we frequently found mutations in the von Hippel-Lindau tumor suppressor gene. No mutation leading to loss of HNF1alpha function was detected by analyzing the integrity of the HNF1alpha transcripts in the RNA derived from RCCs by the protein truncation test. Investigating human RCC cell lines by western blotting and gel retardation assays showed a dramatic loss in the expression of the tissue-specific transcription factor HNF1alpha in eight of 10 cell lines. As the HNF1alpha-related transcription factor HNF1beta was expressed in all these tumor cell lines, the loss of HNF1alpha expression was a specific event and was maintained in RCC cell lines. The loss of HNF1alpha expression in RCC cell lines on the RNA level was confirmed by reverse transcription polymerase chain reaction. We propose that tumor-associated mutations in the HNF1alpha gene do not occur in human RCC and that the loss of function is partially due to a transcriptional inactivation of the HNF1alpha gene.

Renal oncometabolite L-2-hydroxyglutarate imposes a block in kidney tubulogenesis: Evidence for an epigenetic basis for the L-2HG-induced impairment of differentiation

“…In contrast, the activation of Notch signaling may occur when STRAP (serine-threonine kinase associated protein) interacts with the Polycomb complex, so as to inhibit H3K27 methylation, which as a consequence increases the expression of the Notch effectors HES1 and HES5, as observed in colorectal CSCs ( 68 ). Unlike the case with Wnt and Notch signaling, HNF1α- and HNF4α-mediated signaling is reduced in RCCs ( 69 , 70 ), resulting in reduced expression of distinctive RPT genes, such as SLC34A1 (NaPi2a) and SLC22A6 (OAT1) ( 71 ). In contrast, the expression of AQP1 often increases in RCCs ( 72 , 73 ), similar to the increased expression of AQP1 mRNA in RPT matrigel cultures with an L2HGDH KD.…”

HNF1A/CASC2 regulates pancreatic cancer cell proliferation through PTEN/Akt signaling

“…In humans, patients carrying monoallelic mutations in HNF1A suffer from type 3 MODY with renal dysfunctions . Somatic mutations of the HNF1A gene have been reported in hepatoma, colon cancer, and endometrial cancer . Recent GWAS studies have suggested that HNF1A gene is associated with risk of PC, which prompted the current investigation on the functional significance of this gene in PC.…”

“…39 Somatic mutations of the HNF1A gene have been reported in hepatoma, colon cancer, and endometrial cancer. [19][20][21] Recent GWAS studies have suggested that HNF1A gene is associated with risk of PC, 15,16 which prompted the current investigation on the functional significance of this gene in PC. In the present study, we investigated the potential relationship between CASC2 and HNF1A.…”

“…HNF1A silencing by siRNA in hepatocellular carcinoma cells induced overexpression of several genes encoding growth factor receptors, components of the translational machinery, cell cycle, and angiogenesis regulators. 19 Mutations of HNF1A gene were also detected in colorectal cancer with microsatellite instability 20 and in endometrial cancer. 21 This evidence suggests that HNF1A can play a role in cancer development through the regulation of immunity, inflammatory response, and protein folding, as well as cell growth and differentiation.…”

von Hippel-Lindau Protein Maintains Metabolic Balance to Regulate the Survival of Naive B Lymphocytes

“…Loss of VHL leads to constitutive stabilization of HIF-1α and upregulation of HIF-1's target genes even under normoxia. Mutations in vhl gene are found in patients with von Hippel-Lindau disease and in various spontaneous renal cell carcinomas (RCCs) (Gallou et al., 1999, Lemm et al., 1999).…”