scholarly journals KRAS or BRAF mutations cause hepatic vascular cavernomas treatable with MAP2K–MAPK1 inhibition

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Harish Palleti Janardhan ◽  
Xiuling Meng ◽  
Karen Dresser ◽  
Lloyd Hutchinson ◽  
Chinmay M. Trivedi

Human hepatic vascular cavernomas, the most common benign tumor of the liver, were described in the mid-1800s, yet the mechanisms for their formation and effective treatments remain unknown. Here, we demonstrate gain-of-function mutations in KRAS or BRAF genes within liver endothelial cells as a causal mechanism for hepatic vascular cavernomas. We identified gain-of-function mutations in KRAS or BRAF genes in pathological liver tissue samples from patients with hepatic vascular cavernomas. Mice expressing these human KRASG12D or BRAFV600E mutations in hepatic endothelial cells recapitulated the human hepatic vascular cavernoma phenotype of dilated sinusoidal capillaries with defective branching patterns. KRASG12D or BRAFV600E induced “zipper-like” contiguous expression of junctional proteins at sinusoidal endothelial cell–cell contacts, switching capillaries from branching to cavernous expansion. Pharmacological or genetic inhibition of the endothelial RAS–MAPK1 signaling pathway rescued hepatic vascular cavernoma formation in endothelial KRASG12D- or BRAFV600E-expressing mice. These results uncover a major cause of hepatic vascular cavernomas and provide a road map for their personalized treatment.

2021 ◽  
Vol 8 ◽  
Author(s):  
Haijun Mei ◽  
Hua Xian ◽  
Jing Ke

Infantile hemangioma (IH) is a common benign tumor of endothelial cells in infants. Most hemangiomas are self-limited, but a few may develop and lead to serious complications that affect the normal life of children. Therefore, finding an effective treatment strategy for IH is a pressing need. Recent studies have demonstrated that non-coding RNAs affect the progression of multiple tumors. This study aims to investigate the mechanism by which LncRNA-MCM3AP-AS1 promotes glycolysis in the pathogenesis of IH. We first documented that the expression of LncRNA MCM3AP-AS1 was significantly upregulated in IH. Furthermore, we demonstrated that MCM3AP-AS1 bound to miR-106b-3p which promotes glycolysis in IH. In addition, we found that inhibition of HIF-1α contributed to the transformation of glycolysis to normal aerobic oxidation, partially reversed the promoting effect on glycolysis by the up-regulation of LncRNA MCM3AP-AS1 in IH disease. More importantly, we demonstrated this phenomenon existed in IH patients. Taken together, we demonstrate that LncRNA-MCM3AP-AS1 promotes the progression of infantile hemangiomas by increasing the glycolysis via regulating miR-138-5p/HIF-1α axis.


2014 ◽  
Vol 52 (01) ◽  
Author(s):  
V Sterzer ◽  
M Alsamman ◽  
R Weiskirchen ◽  
C Trautwein ◽  
D Scholten

1995 ◽  
Vol 319 (1) ◽  
pp. 63-73 ◽  
Author(s):  
Z.C. Chroneos ◽  
J.W. Baynes ◽  
S.R. Thorpe

2003 ◽  
Vol 66 (6) ◽  
pp. 1045-1054 ◽  
Author(s):  
Michael J Duryee ◽  
Lynell W Klassen ◽  
Thomas L Freeman ◽  
Monte S Willis ◽  
Dean J Tuma ◽  
...  

2012 ◽  
Vol 56 ◽  
pp. S311
Author(s):  
J. Liu ◽  
M. Jiang ◽  
Z. Ma ◽  
J. Schlaak ◽  
M. Roggendorf ◽  
...  

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lauren Y. Cheng ◽  
Lauren E. Haydu ◽  
Ping Song ◽  
Jianyi Nie ◽  
Michael T. Tetzlaff ◽  
...  

AbstractMutations in the BRAF gene at or near the p. V600 locus are informative for therapy selection, but current methods for analyzing FFPE tissue DNA generally have a limit of detection of 5% variant allele frequency (VAF), or are limited to the single variant (V600E). These can result in false negatives for samples with low VAFs due to low tumor content or subclonal heterogeneity, or harbor non-V600 mutations. Here, we show that Sanger sequencing using the NuProbe VarTrace BRAF assay, based on the Blocker Displacement Amplification (BDA) technology, is capable of detecting BRAF V600 mutations down to 0.20% VAF from FFPE lymph node tissue samples. Comparison experiments on adjacent tissue sections using BDA Sanger, immunohistochemistry (IHC), digital droplet PCR (ddPCR), and NGS showed 100% concordance among all 4 methods for samples with BRAF mutations at ≥ 1% VAF, though ddPCR did not distinguish the V600K mutation from the V600E mutation. BDA Sanger, ddPCR, and NGS (with orthogonal confirmation) were also pairwise concordant for lower VAF mutations down to 0.26% VAF, but IHC produced a false negative. Thus, we have shown that Sanger sequencing can be effective for rapid detection and quantitation of multiple low VAF BRAF mutations from FFPE samples. BDA Sanger method also enabled detection and quantitation of less frequent, potentially actionable non-V600 mutations as demonstrated by synthetic samples.


1997 ◽  
Vol 272 (3) ◽  
pp. G605-G611 ◽  
Author(s):  
A. T. Eakes ◽  
K. M. Howard ◽  
J. E. Miller ◽  
M. S. Olson

Activation of endothelin (ET) receptors in the liver causes vasoconstriction, glucose production, and lipid and peptide mediator synthesis. In the intact rat, a bolus infusion of endotoxin into a mesenteric vein served as an acute exposure model of endotoxemia. In response to this challenge, a ninefold increase in hepatic ET-1 mRNA occurred within 3 h. The plasma level of immunoreactive ET-1 (irET-1) increased correspondingly by 8.5-fold within 6 h. ET-1 mRNA levels in liver endothelial cells (EC) isolated from livers of endotoxin-treated rats at various times after endotoxin challenge showed a more gradual increase. Northern blot analyses of the major liver cell types demonstrated that ET-1 mRNA was most abundant in the EC. The present results document a significant increase in the circulating level of irET-1 during episodes of endotoxemia. The increased hepatic ET-1 production in response to endotoxin infusion suggests that ET-1 produced in the liver could make a significant contribution to the plasma irET-1 and may be an important component in the hepatic responses to systemic trauma.


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