Disruption of Dicer1 induces dysregulated fetal gene expression and promotes hepatocarcinogenesis.
OBJECTIVE
Growing evidence suggests that microRNAs coordinate various biological processes in the liver. We describe experiments to address the physiologic roles of these new regulators of gene expression in the liver that are as of yet largely undefined.


METHODS
We disrupted Dicer, an enzyme essential for the processing of microRNAs, in hepatocytes using a conditional knockout mouse model to elucidate the consequences of loss of microRNAs.


RESULTS
The conditional knockout mouse livers showed the efficient disruption of Dicer1 at 3 weeks after birth. This resulted in prominent steatosis and the depletion of glycogen storage. Dicer1-deficient liver exhibited increased growth-promoting gene expression and the robust expression of fetal stage-specific genes. The consequence of Dicer elimination included both increased hepatocyte proliferation and overwhelming apoptosis. Over time, Dicer1-expressing wild-type hepatocytes that had escaped Cre-mediated recombination progressively repopulated the entire liver. Unexpectedly, however, two thirds of the mutant mice spontaneously developed hepatocellular carcinomas derived from residual Dicer1-deficient hepatocytes at 1 year of age.


CONCLUSIONS
Dicer and microRNAs have critical roles in hepatocyte survival, metabolism, developmental gene regulation, and tumor suppression in the liver. Loss of Dicer primarily impairs hepatocyte survival but can promote hepatocarcinogenesis in cooperation with additional oncogenic stimuli.
Sekine
Shigeki
S
Pathology Division, National Cancer Center Research Institute, Tokyo, Japan. ssekine@ncc.go.jp
Ogawa
Reiko
R
Ito
Rie
R
Hiraoka
Nobuyoshi
N
McManus
Michael T
MT
Kanai
Yae
Y
Hebrok
Matthias
M
D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D011247:Pregnancy; D011270:Pregnancy, Animal; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics*; D012680:Sensitivity and Specificity
D001786:Blood Glucose; D035683:MicroRNAs; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases