However, because the net result of global miRNA deficiency in hepatocytes was impaired

S phase Y-27632 price entry, loss of miR-378 appears to be insufficient to compensate loss of miR-21 during liver regeneration. Specific inhibition of miR-21 and miR-378 in vivo could be used to delineate their individual contributions to regulation of liver regeneration.30 Because a single miRNA typically targets many genes, the effects of miR-21 and miR-378 during liver regeneration are most likely not restricted to inhibition of Btg2 and Odc1. For example, in addition to Tgfbi and Smad7, the TargetScan algorithm predicts Tgfbr2, Acvr1c (activin A receptor 1C), and Acvr2a (activin A receptor 2A) as direct and conserved miR-21 targets

involved in TGFβ and activin signaling. miR-21 might target these genes to limit the inhibitory effect of TGFβ and activin signaling on G1 to S phase transition of hepatocytes after 2/3 PH.25 The levels of the proliferation-promoting gene Ccnd1 were increased in hepatocytes with global miRNA deficiency before 2/3 PH. Our selleck miRNA profiling revealed that miR-16, an miRNA known to inhibit Ccnd1 in the prostate, is expressed in the liver.31 Thus, loss of miR-16 may explain de-repression of Ccnd1 in Dgcr8del/fl, Alb-Cre+/− mice. In analogy, it is possible that loss of other miRNAs normally expressed in hepatocytes but not induced by 2/3 PH may contribute to impaired liver regeneration in Dgcr8del/fl, Alb-Cre+/− mice. This could explain the spontaneous oval cell activation in a subset of Dgcr8del/fl, Alb-Cre+/− mice. In addition, mouse miRNAs continue to be identified and we cannot rule out that miRNAs not represented on our arrays play a role in liver regeneration. However, in contrast to findings after DGCR8 inactivation in the skin,32 miR-21 was depleted in whole liver samples of mice 上海皓元医药股份有限公司 with hepatocyte-specific DGCR8 deficiency. This shows that miR-21 is mainly

expressed in hepatocytes in the liver and supports our conclusion that miR-21 directly regulates cell cycle progression in hepatocytes. Specific induction of miR-21 in G1 phase after 2/3 PH and impaired G1 to S phase transition in both hepatocytes with global miRNA deficiency and in those with FoxM1 deficiency further suggest that miR-21 plays a leading role in miRNA regulation of liver regeneration. Our analyses focused on miRNA target genes that are conserved between mouse and human. Although little has been reported about miR-378′s regulation or function, the expression of miR-21 is known to be increased in primary human liver cancer.33, 34 Moreover, miR-21 has been shown to promote proliferation of human liver cancer cell lines by inhibition of the phosphatase and tensin homolog (PTEN) tumor suppressor.33 Therefore, it is likely that miR-21 inhibits Btg2, and potentially other regulators of hepatocyte proliferation, also in human liver regeneration. The authors thank Dr.