A quantitative gene expression study suggests a role for angiopoietins in focal nodular hyperplasia.
OBJECTIVE
Although the pathogenesis of focal nodular hyperplasia (FNH) of the liver remains unclear, a vascular mechanism has been suspected. To gain insight into the pathogenesis of FNH, we performed a large-scale quantitative study of gene expression in FNH.


METHODS
Quantitative expression level of 209 selected genes was assessed using real-time reverse-transcription polymerase chain reaction in 14 cases of FNH and compared with their expression level in 13 cases of liver cirrhosis, 4 adenomas, and 15 hepatocellular carcinomas.


RESULTS
Among the 7 genes, the expression of which was significantly up-regulated or down-regulated in FNH, the most informative markers for the diagnosis of FNH as assessed using the receiving operative curve and area under the curve (AUC) were angiopoietin-1 (Ang-1; AUC, 0.82) and angiopoietin-2 (Ang-2; AUC, 0.80). These 2 genes are involved in the regulation of vasculogenesis. In FNH, Ang-1 was significantly up-regulated, Ang-2 was down-regulated, and the Ang-1/Ang-2 ratio was highly and specifically increased in FNH compared with normal liver or other groups of lesions (FNH, 15.2-fold increase; HCC, 2.78; adenoma, 2.28; cirrhosis, 1.92; P < 0.01 for FNH vs. all groups, analysis of variance). Tie-2 messenger RNA, the receptor of Ang-1 and Ang-2, was detected at the same level in FNH as in normal liver. Ang-1 protein was detected on Western blot of FNH and expressed by endothelial cells of dystrophic vessels and sinusoids as shown by immunohistochemistry.


CONCLUSIONS
A specific increase of Ang-1/Ang-2 ratio in FNH, in the presence of the functional Tie-2 receptor, might be involved in the formation of hyperplastic and dystrophic vessels of FNH.
Paradis
Valérie
V
Service d'Anatomie Pathologique and Service de Chirurgie, Hôpital Beaujon, Clichy, France. vparadis@teaser.fr
Bièche
Ivan
I
Dargère
Delphine
D
Laurendeau
Ingrid
I
Nectoux
Juliette
J
Degott
Claude
C
Belghiti
Jacques
J
Vidaud
Michel
M
Bedossa
Pierre
P
D000236:Adenoma / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D043925:Angiogenesis Inducing Agents / Q000235:genetics / Q000378:metabolism*; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D020518:Focal Nodular Hyperplasia / Q000235:genetics* / Q000503:physiopathology*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D042787:Receptor, TIE-2
D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D008562:Membrane Glycoproteins; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2