The Fox Genes in the Liver: From Organogenesis to Functional Integration
ABSTRACT Formation and function of the liver are highly controlled, essential processes. Multiple signaling pathways and transcriptional regulatory networks cooperate in this complex system. The evolutionarily conserved FOX, for Forkhead bOX, class of transcriptional regulators is critical to many aspects of liver development and function. The FOX proteins are small, mostly monomeric DNA binding factors containing the so-called winged helix DNA binding motif that distinguishes them from other classes of transcription factors. We discuss the biochemical and genetic roles of Foxa, Foxl1, Foxm1, and Foxo, as these have been shown to regulate many processes throughout the life of the organ, controlling both formation and function of the liver.
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ABSTRACT: Recent studies have demonstrated direct reprogramming of fibroblasts into a range of somatic cell types, but to date stem or progenitor cells have only been reprogrammed for the blood and neuronal lineages. We previously reported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 in p19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liver organogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells (iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bidirectional differentiation into both hepatocytic and cholangiocytic lineages. In the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells. They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineage conversion into bipotential expandable iHepSCs provides a strategy to enable efficient derivation of both hepatocytes and cholangiocytes for use in disease modeling and tissue engineering.Cell stem cell 07/2013; DOI:10.1016/j.stem.2013.06.017 · 23.56 Impact Factor
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ABSTRACT: Foxp1 and Foxq1 are two multifunctional molecules of "forkhead box(Fox)" family. The objective of this paper was to construct the lentiviral vectors expressing RNA interference(RNAi) against Foxp1 or Foxq1 genes, and the effects of both vectors with two RNAis on the proliferation, migration and apoptosis of 7721 hepatocarcinoma cell line was evaluated. Six target sequences against human Foxp1/Foxq1 mRNA were designed respectively and six pairs of their corresponding double-strand DNA oligo(siRNA) were synthesized prior to being transfected into 7721 cells with lipo2000,then a most efficient siRNA were selected to be subcloned into pLL3.7-GFP/Lenti plasmids. These plasmids were transfected into 293T cells to package lentiviral particles for subsequent transfection into 7721 cells after their sequences were confirmed. The expression of Foxp1and Foxq1 genes in the transfected cells were identified by real-time PCR. The migration, infiltration, viability and apoptosis of the transfected cells were assessed by wound healing assay, Transwell assay, CCK-8 assay and flow cytometry. Sequencing results showed that lentiviral vectors contained Foxp1 or Foxq1 gene. After being transfected into 7721 cells, Foxp1 and Foxq1 expression were significantly down-regulated by siRNA-823 and siRNA-834. The migration and infiltration ability, and the viability of 7721 cells transfected with two siRNAs were significantly suppressed; flow cytometry assay exhibited the apoptosis rate of transfected 7721 cells with the lentivirus RNAi vector of Foxp1 or Foxq1was increased. All the results showed that the lentivirus RNAi vectors of Foxp1 and Foxq1 were able to inhibit the expression of Foxp1 and Foxq1 in 7721 cells efficiently, and the down-regulation of either Foxp1 or Foxq1 resulted in suppression of migration, infiltration and viability of 7721 cells and an increase in cell apoptosis. Our data indicated that both Foxp1 and Foxq1 genes played an oncogenic role in hepatocarcinoma cells, which proposed the two genes as new therapeutic targets for the cancer.Experimental and Molecular Pathology 11/2013; DOI:10.1016/j.yexmp.2013.10.015 · 2.88 Impact Factor
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ABSTRACT: Human Forkhead-Box Class O (FoxO) transcription factors, activated in response to a wide range of external stimuli, like growth factors, insulin, nutrient levels and oxidative stress, are able to control several specific gene-expression programs. Besides their clear implication in metabolic processes, they appear to play a relevant role in tumour suppression by upregulation of genes involved in cell cycle arrest or apoptosis. Recent research efforts provide new insights into the molecular modulation of FoxO in liver cancer and disclose potential opportunities for developing new antitumor drugs. Through an intricate regulatory model, achieved via several post-translational modifications, including phosphorylation, acetylation, and ubiquitination, which control their subcellular localization and DNA binding activity, FoxO factors act as tumour suppressors. Low levels of FoxOs are associated with poor prognosis in cancer patients, and seem to confer chemotherapy resistance. Within FoxO members, FoxO3a appears to present anti-tumour properties in hepatocellular carcinoma, inducing the expression of pro-apoptotic genes, or interfering with signaling cascades commonly altered in this disease such as Wnt/β-catenin, PI3K/AKT/mTOR or MAPKs pathways. Here, we describe the main mechanisms of FoxO proteins regulation, and their cross link with altered pathways in liver cancer. Moreover, based on the current knowledge of FoxO modulation, emphasis is placed on the development of novel agents which specifically activate FoxO family members and could be useful in the treatment of hepatocarcinoma.Current Medicinal Chemistry 04/2014; 21(10):1231-1240. DOI:10.2174/0929867321666131228205703 · 3.72 Impact Factor