• Cytochrome P450
• Hepatic progenitor cell
• Hepatocyte
• Liver regeneration
• Pluripotent stem cell

• Humans
• Pluripotent Stem Cells
• Embryonic Stem Cells
• Liver
• Drug Discovery
• Eye Diseases, Hereditary

• CRISPR/Cas9
• RNAi strategies
• antisense oligonucleotide (ASO)
• aptamer
• riboswitch
• ribozyme
• small interfering RNA (siRNA)

• HCC
• HDAC
• HDACI
• anticancer
• deacetylase
• epigenetic
• hepatocellular carcinoma
• histone
• inhibitors
• targeted
• therapeutics

• dissolved oxygen
• fetal hepatic organoids
• human pluripotent stem cells
• red blood cells
• stirred tank bioreactor

• Bioreactors
• Humans
• Liver/cytology
• Liver/metabolism
• Organoids/cytology
• Organoids/metabolism
• Oxygen/metabolism
• Oxygen/pharmacology
• Pluripotent Stem Cells/cytology
• Pluripotent Stem Cells/metabolism

• Cancer stem cells
• Signaling pathways
• Therapy

Lipedema is a chronic, progressive disease of adipose tissue with lack of consistent diagnostic criteria. The aim of this study was a thorough comparative characterization of extracellular microRNAs (miRNAs) from the stromal vascular fraction (SVF) of healthy and lipedema adipose tissue. For this, we analyzed 187 extracellular miRNAs in concentrated conditioned medium (cCM) and specifically in small extracellular vesicles (sEVs) enriched thereof by size exclusion chromatography. No significant difference in median particle size and concentration was observed between sEV fractions in healthy and lipedema. We found the majority of miRNAs located predominantly in cCM compared to sEV enriched fraction. Surprisingly, hierarchical clustering of the most variant miRNAs showed that only sEVmiRNA profiles – but not cCMmiRNAs – were impacted by lipedema. Seven sEVmiRNAs (miR–16-5p, miR-29a-3p, miR-24-3p, miR-454-p, miR–144-5p, miR-130a-3p, let-7c-5p) were differently regulated in lipedema and healthy individuals, whereas only one cCMmiRNA (miR-188-5p) was significantly downregulated in lipedema. Comparing SVF from healthy and lipedema patients, we identified sEVs as the lipedema relevant miRNA fraction. This study contributes to identify the potential role of SVF secreted miRNAs in lipedema.

• Cancer
• Metabolism reprogramming
• Resistance
• Stemness
• Tumor microenvironment
• Wnt

• Disease Progression
• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Tumor Microenvironment
• Wnt Signaling Pathway

• focal nodular hyperplasia
• hepatocellular carcinoma
• hereditary hemorrhagic telangiectasia
• ischemic liver cirrhosis theory
• vascular malformation

• Aged
• Carcinoma, Hepatocellular/complications
• Carcinoma, Hepatocellular/diagnosis
• Diagnosis, Differential
• Endoscopy, Gastrointestinal
• Fatal Outcome
• Female
• Humans
• Liver Neoplasms/complications
• Liver Neoplasms/diagnosis
• Magnetic Resonance Imaging
• Telangiectasia, Hereditary Hemorrhagic/complications
• Telangiectasia, Hereditary Hemorrhagic/diagnosis
• Tomography, X-Ray Computed

• Axin1, axis inhibition protein 1
• DKK-1, Dickkopf Wnt signaling pathway inhibitor 1
• DVL2, disheveled 2
• FADD, Fas-associated protein with death domain
• HCC
• HCC, hepatocellular carcinoma
• Human
• KD, knock-down
• LDH, lactate dehydrogenase
• LRP6
• LRP6, low-density lipoprotein receptor (LDLR)-related protein 6
• MCL-1, myeloid cell leukemin-1
• NAFLD, non-alcoholic fatty liver disease
• Nude mice
• PCNA, proliferating cell nuclear antigen
• S-allylmercaptocysteine
• SAC, S-allylcysteine
• SAMC, S-allylmercaptocysteine
• SPR, surface plasmon resonance
• TCF/LEF, T-cell factor/lymphoid enhancing factor
• TSA, thermal shift assay
• Tm, melting temperature
• Wnt

• Wnt/β-catenin
• gadoxetic acid-enhanced magnetic resonance imaging
• hepatocellular carcinoma
• molecular therapy

Oligodendrocyte‐formed myelin sheaths play important roles in the neuronal functions in the central nervous system. In demyelinating diseases, such as Multiple Sclerosis, the myelin sheaths are damaged and the remyelinating process is somehow hindered. Restoration of the myelin sheaths requires the differentiation of the oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). To discover small molecule compounds that might promote the OPC to OL differentiation, a high‐throughput screening system is established and L‐ascorbyl‐2‐phosphate (As‐2P), a stable form of Vitamin C (Vc), is found to greatly enhance the OPC to OL differentiation. As‐2P promotes gradual expression of OL lineage markers, including O4, CNPase and MBP, in a dose‐ and time‐dependent manner. It also facilitates the formation of myelin sheaths in OPC‐neuron co‐culture. As‐2P also promotes the repair of the myelin sheaths in vivo and provides significant therapeutic effect in a cuprizone‐mediated demyelination animal model. Interestingly, As‐2P's function in promoting OPC differentiation is not related to its antioxidant activity. And an intracellular rather than an extracellular mechanism might be involved. Considering the safe use of Vc as a dietary supplement for many years, it might also be used as an alternative medicine for CNS demyelinating diseases.

• differentiation
• myelin
• oligodendrocyte
• oligodendrocyte progenitor cell
• remyelination
• vitamin C

Hepatic progenitor cells (HPCs) are small cells with a relative large oval nucleus and a scanty cytoplasm situated in the canals of Hering that express markers of (immature) hepatocytes and cholangiocytes. HPCs are present in large numbers in alcoholic steatohepatitis (ASH), one of the leading causes of chronic liver disease. To date, the mechanisms responsible for proliferation and differentiation of human HPCs are still poorly understood and the role of HPCs in ASH development is unknown. In this study, we aimed to characterise human HPCs and their interactions with other cells through comparison, on both protein and RNA level, of HPC-enriched cell populations from adult human liver tissue using different isolation methods. Fresh human liver tissue was collected from ASH explant livers and HPC-enriched cell populations were obtained via four different isolation methods: side population (SP), epithelial cell adhesion molecule (EpCAM) and trophoblast antigen 2 (TROP-2) membrane marker isolation and laser capture microdissection. Gene expression profiles of fluorescent-activated cell-sorted HPCs, whole liver extracts and laser microdissected HPC niches were determined by RNA-sequencing. Immunohistochemical evaluation of the isolated populations indicated the enrichment of HPCs in the SP, EpCAM⁺ and TROP-2⁺ cell populations. Pathway analysis of the transcription profiles of human HPCs showed an enrichment and activation of known HPC pathways like Wnt/β-catenin, TWEAK and HGF. Integration of the HPC niche profile suggests autocrine signalling by HPCs (TNFα, PDGFB and VEGFA) as well as paracrine signalling from the surrounding niche cells including MIF and IGF-1. In addition, we identified IL-17 A signalling as a potentially novel pathway in HPC biology. In conclusion, we provide the first RNA-seq-based, comparative transcriptome analysis of isolated human HPCs from ASH patients and revealed active signalling between HPCs and their surrounding niche cells in ASH livers and suggest that HPCs can actively contribute to liver inflammation.

UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) plays a crucial role in DNA methylation, chromatin remodeling and gene expression and is aberrantly upregulated in various types of human cancers. However, the precise role of UHRF1 in cancer remains controversial. In this study, we observed that hypoxia-induced downregulation of UHRF1 contributes to the induction of the epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma cells. By negatively modulating UHRF1 expression, we further showed that UHRF1 deficiency in itself is sufficient to increase the migratory and invasive properties of cells via inducing EMT, increasing the tumorigenic capacity of cells and leading to the expansion of cancer stem-like cells. Epigenetic changes caused by UHRF1 deficiency triggered the upregulation of CXCR4, thereby activating AKT and JNK to increase the expression and secretion of IL-6. In addition, IL-6 readily activated the JAK/STAT3/Snail signaling axis, which subsequently contributed to UHRF1 deficiency-induced EMT. Our results collectively demonstrate that UHRF1 deficiency may play a pivotal role in the malignant alteration of cancer cells.

• Epithelial–mesenchymal transition
• HNF4α
• Liver stem cells
• Snail
• Tg737

• CD133(+) cells
• HCV
• Hepatocellular carcinoma

• AC133 Antigen/metabolism
• Adult
• Aged
• Aged, 80 and over
• Biomarkers
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/pathology
• Case-Control Studies
• Cluster Analysis
• Female
• Gene Expression Profiling
• Hepatitis C/complications
• Humans
• Immunomagnetic Separation
• Immunophenotyping
• Liver Function Tests
• Liver Neoplasms/etiology
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Neoplastic Cells, Circulating/metabolism
• Neoplastic Cells, Circulating/pathology
• Neoplastic Stem Cells/metabolism
• Transcriptome

Reliable biological markers that predict breast cancer (BC) outcomes after multidisciplinary therapy have not been fully elucidated. We investigated the association between casein kinase 1 epsilon (CK1ε) and the risk of recurrence in patients with BC. Using 168 available tumor samples from patients with BC treated with surgery +/− chemo(radio)therapy, we scored the CK1ε expression as high (≥1.5) or low (<1.5) using an immunohistochemical method. Kaplan-Meier analysis was performed to assess the risk of relapse, and Cox proportional hazards analyses were utilized to evaluate the effect of CK1ε expression on this risk. The median age at diagnosis was 60 years (range 35-96). A total of 58% of the patients underwent breast conservation surgery, while 42% underwent mastectomy. Adjuvant chemotherapy and radiation therapy were administered in 101 (60%) and 137 cases (82%), respectively. Relapse was observed in 24 patients (14%). Multivariate analysis found high expression of CK1ε to be associated with a statistically significant higher disease-free survival (DFS) in BC patients with wild-type p53 (Hazard ratio [HR] = 0.33; 95% CI, 0.12-0.91; P = 0.018) or poor histological differentiation ([HR] = 0.34; 95% CI, 0.12-0.94; P = 0.039) or in those without adjuvant chemotherapy ([HR] = 0.11; 95% CI, 0.01-0.97; P = 0.006). Our data indicate that CK1ε expression is associated with DFS in BC patients with wild-type p53 or poor histological differentiation or in those without adjuvant chemotherapy and thus may serve as a predictor of recurrence in these subsets of patients.

• breast cancer
• casein kinase 1 epsilon (CK1ε)
• disease-free survival
• outcome
• relapse

• bioinformatics framework
• cancer cells
• in silico experiments
• intracellular communication

• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Movement/radiation effects
• Cell Proliferation/genetics
• Cell Proliferation/radiation effects
• Ferric Compounds/administration & dosage
• Frizzled Receptors/antagonists & inhibitors
• Frizzled Receptors/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Iron/administration & dosage
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Matrix Metalloproteinase 9/biosynthesis
• Matrix Metalloproteinase 9/genetics
• Oxides/administration & dosage
• RNA, Small Interfering/genetics
• Radiation Tolerance/drug effects
• Ultrasonic Waves

• Apoptosis/drug effects
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Cyclin D1/biosynthesis
• Cyclin D1/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms/drug therapy
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Matrix Metalloproteinase 9/biosynthesis
• Matrix Metalloproteinase 9/genetics
• Sulfonamides/administration & dosage
• Wnt Signaling Pathway/drug effects

Activation of the hypoxia-inducible factor (HIF)-pathway in hepatocellular carcinoma (HCC) induces therapy resistant tumours, characterized by increased liver progenitor cell (LPCs) characteristics and poor prognosis. We previously reported corresponding results in mice with HCC in which hypoxia was mimicked by prolyl hydroxylase domain (PHD) inhibition. Here, we aimed at investigating whether induction of LPC characteristics occurs during the onset of hepatocarcinogenesis and if this is associated with activation of Notch signalling. Dietheylnitrosamine (DEN) was used to induce hepatic tumours in PHD2 haplodeficient (PHD2^+/-) mice which were euthanized at 5, 10, 15 and 17 weeks following DEN during neoplastic transformation, before tumour formation. Neoplasia and mRNA expression of LPC and Notch markers were evaluated by histology and qPCR on isolated livers. PHD2 haplodeficiency resulted in enhanced expression of HIF target genes after 17 weeks of DEN compared to wild type (WT) littermates but had no effect on the onset of neoplastic transformation. The mRNA expression of Afp and Epcam was increased at all time points following DEN whereas CK19, Prom1 and Notch3 were increased after 17 weeks of DEN, without difference between PHD2^+/- and WT mice. MDR1 mRNA expression was increased in all DEN treated mice compared to saline control with increased expression in PHD2^+/- compared to WT from 15 weeks. These results indicate that the effects of PHD2 haplodeficiency on the expression of LPC and Notch markers manifest during tumour nodule formation and not early on during neoplastic transformation.

• diethylnitrosamine
• hepatocarcinogenesis
• hypoxia
• liver progenitor cells
• notch
• prolyl hydroxylase domain

Transforming growth factor-beta 1 (TGF-β1) plays a central role in hepatic progenitor cells- (HPCs-) mediated liver repair and fibrosis. However, different effects of TGF-β1 on progenitor cells have not been described. In this study, both in vitro (HPCs cocultured with hepatic stellate cells (HSCs) in transwells) and in vivo (CCl₄-injured liver fibrosis rat) systems were used to evaluate the impacts. We found that HPCs pretreated with TGF-β1 for 12 hours inhibited the activation of HSCs, while sensitization for 48 hours increased the activation of HSCs. Consistent with these in vitro results, the in vivo fibrosis rat model showed the same time-dependent dual effect of TGF-β1. Regression of liver fibrosis as well as normalization of serum aminotransferase and albumin levels was detected in the rats transplanted with HPCs pretreated with TGF-β1 for 12 hours. In contrast, severe liver fibrosis and elevated collagen-1 levels were detected in the rats transplanted with HPCs pretreated with TGF-β1 for 48 hours. Furthermore, the TGF-β1-pretreated HPCs were shown to deactivate HSCs via enhancing SERPINE1 expression. Inhibition of SERPINE1 reversed the deactivation response in a dose-dependent manner.

Hepatocellular carcinoma (HCC) is a type of malignant cancer. Notch signaling is aberrantly expressed in HCC tissues with more evidence showing that this signaling plays a critical role in HCCs. In the present study, we investigate the effects of the anti-convulsant drug valproic acid (VPA) in HCC cells and its involvement in modulating Notch signaling. We found that VPA, acting as a histone deacetylase (HDAC) inhibitor, induced a decrease in HDAC4 and an increase in acetylated histone 4 (AcH4) and suppressed HCC cell growth. VPA also induced down-regulation of Notch signaling via suppressing the expression of Notch1 and its target gene HES1, with an increase of tumor suppressor p21 and p63. Furthermore, Notch1 activation via overexpressing Notch1 active form ICN1 induced HCC cell proliferation and anti-apoptosis, indicating Notch signaling played an oncogenic role in HCC cells. Meanwhile, VPA could reverse Notch1-induced increase of cell proliferation. Interestingly, VPA was also observed to stimulate the expression of G protein-coupled somatostatin receptor type 2 (SSTR2) that has been used in receptor-targeting therapies. This discovery supports a combination therapy of VPA with the SSTR2-targeting agents. Our in vitro assay did show that the combination of VPA and the peptide-drug conjugate camptothecin-somatostatin (CPT-SST) displayed more potent anti-proliferative effects on HCC cells than did each alone. VPA may be a potential drug candidate in the development of anti-HCC drugs via targeting Notch signaling, especially in combination with receptor-targeting cytotoxic agents.

• HDAC inhibitor
• Notch signaling
• hepatocellular carcinoma
• receptor-targeting.
• valproic acid

Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. In ninety percent of the cases it develops as a result of chronic liver damage and it is thus a typical inflammation-related cancer characterized by the close relation between the tumor microenvironment and tumor cells. The stromal environment consists out of several cell types, including hepatic stellate cells, macrophages and endothelial cells. They are not just active bystanders in the pathogenesis of HCC, but play an important and active role in tumor initiation, progression and metastasis. Furthermore, the tumor itself influences these cells to create a background that is beneficial for sustaining tumor growth. One of the key players is the hepatic stellate cell, which is activated during liver damage and differentiates towards a myofibroblast-like cell. Activated stellate cells are responsible for the deposition of extracellular matrix, increase the production of angiogenic factors and stimulate the recruitment of macrophages. The increase of angiogenic factors (which are secreted by macrophages, tumor cells and activated stellate cells) will induce the formation of new blood vessels, thereby supplying the tumor with more oxygen and nutrients, thus supporting tumor growth and offering a passageway in the circulatory system. In addition, the secretion of chemokines by the tumor cells leads to the recruitment of tumor associated macrophages. These tumor associated macrophages are key actors of cancer-related inflammation, being the main type of inflammatory cells infiltrating the tumor environment and exerting a tumor promoting effect by secreting growth factors, stimulating angiogenesis and influencing the activation of stellate cells. This complex interplay between the several cell types involved in liver cancer emphasizes the need for targeting the tumor stroma in HCC patients.

• Hepatocellular carcinoma
• Stellate cells
• Cirrhosis
• Angiogenesis
• Macrophages
• Inflammation

Liver cancer is an aggressive disease with a high mortality rate. Management of liver cancer is strongly dependent on the tumor stage and underlying liver disease. Unfortunately, most cases are discovered when the cancer is already advanced, missing the opportunity for surgical resection. Thus, an improved understanding of the mechanisms responsible for liver cancer initiation and progression will facilitate the detection of more reliable tumor markers and the development of new small molecules for targeted therapy of liver cancer. Recently, there is increasing evidence for the “cancer stem cell hypothesis”, which postulates that liver cancer originates from the malignant transformation of liver stem/progenitor cells (liver cancer stem cells). This cancer stem cell model has important significance for understanding the basic biology of liver cancer and has profound importance for the development of new strategies for cancer prevention and treatment. In this review, we highlight recent advances in the role of liver stem cells in hepatocarcinogenesis. Our review of the literature shows that identification of the cellular origin and the signaling pathways involved is challenging issues in liver cancer with pivotal implications in therapeutic perspectives. Although the dedifferentiation of mature hepatocytes/cholangiocytes in hepatocarcinogenesis cannot be excluded, neoplastic transformation of a stem cell subpopulation more easily explains hepatocarcinogenesis. Elimination of liver cancer stem cells in liver cancer could result in the degeneration of downstream cells, which makes them potential targets for liver cancer therapies. Therefore, liver stem cells could represent a new target for therapeutic approaches to liver cancer in the near future.

• Liver cancer
• Liver stem cells
• Hepatocarcinogenesis
• Tumorigenic transformation
• Transdifferentiation

• Cancer stem cell
• Chemo-resistance
• Chemotherapy
• Chromatin remodelling
• DNA methylation
• Epigenetic reprogramming