Together with the well-known down-regulation of miR-199a/b-3p in nonasiatic HCC collectives,14 these data highlight the importance of miR-199a/b-3p expression in liver diseases and HCC. In further experiments, the authors explored the functional significance of miR-199a/b-3p down-regulation in HCC. First, restoration of miR-199a/b-3p expression in HCC cell lines inhibited cell growth, induced apoptosis, and inhibited

cell cycle progression, indicating that miR-199a/b-3p this website may function as a tumor suppressor in vitro. Moreover, infection of a human HCC-bearing nude mouse model (SMMC-LTNM model) with an adeno-associated virus 8 (AAV-8) vector system to overexpress miR-199a/b-3p led to inhibition of tumor growth and reduction of serum alpha-fetoprotein,

even after a single selleck chemical tail vein injection. As pointed out before, miRNAs can suppress transcription and translation of hundreds of target mRNAs. To identify the relevant targets of miR-199a/b-3p in the context of hepatocarcinogenesis, the authors followed different approaches, including in silico analysis of databases, gene enrichment, and ontology analysis. By combining these respective approaches, the authors could identify the mitogen-activated protein kinase (MAPK) signaling pathway as a potential target of miR-199a/b-3p. Of this pathway, only PAK4 (p21 protein [Cdc42/Rac]-activated kinase 4) contains putative miR-199a/b-3p target sites. Strikingly, expression of PAK4 could not only be down-regulated by miR-199a/b-3p transfection and overexpression, crotamiton but high PAK4 protein levels also correlated with low miR-199a/b-3p expression in HCC samples. The pathophysiological significance of this finding was highlighted by the fact that intratumoral injection of cholesterol-conjugated small, interfering RNA against PAK4 led to inhibited tumor growth and reduced serum

alpha-fetoprotein levels in the SMMC-LTNM model. On a molecular level, inhibition of miR-199a/b-3p or overexpression of PAK4 inhibited the activation of the Raf/MEK/ERK (extracellular signal-regulated kinase) cascade, which is believed to promote hepatocarcinogenesis in humans.14 Interestingly, besides PAK4, miR-199a/b-3p also targets signaling of c-met and mammalian target of rapamycin, and it seems likely that a deregulation in the whole network of these “pro-oncogenic” pathways rather than a down-regulation of a single gene contribute to the procarcinogenic effects of miR-199a/b-3p silencing in HCC (Fig. 1). HCC represents the fifth most common cause for cancer-related death worldwide, and in some African or Asian countries, HCC is even the leading cause of cancer-related morbidity.