Hepatic Cell News Volume 3.19 | May 31 2019

TOP STORY

Modeling Steatohepatitis in Humans with Pluripotent Stem Cell-Derived Organoids

Scientists developed a reproducible method to derive multi-cellular human liver organoids composed of hepatocyte-, stellate-, and Kupffer-like cells that exhibit transcriptomic resemblance to in vivo-derived tissues. Under free fatty acid treatment, organoids, but not reaggregated cocultured spheroids, recapitulated key features of steatohepatitis, including steatosis, inflammation, and fibrosis phenotypes in a successive manner. [Cell Metab] Abstract | Press Release | Graphical Abstract

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LncRNA PSTAR Promotes p53 Signaling by Inhibiting hnRNP K deSUMOylation and Suppresses Hepatocellular Carcinoma

Investigators demonstrated that a long non-coding RNA (lncRNA), named p53-stabilizing and activating RNA (PSTAR), inhibited hepatocellular carcinoma cell proliferation and tumorigenicity through inducing p53-mediated cell cycle arrest. They revealed that PSTAR could bind to hnRNP K and enhance its SUMOylation, and thereby strengthen the interaction between hnRNP K and p53, which ultimately led to the accumulation and transactivation of p53. [Hepatology] Abstract

A Noncoding Regulatory RNAs Network Driven by Circ-CDYL Acts Specifically in the Early Stages Hepatocellular Carcinoma

A treatment incorporating Circ-CDYL interference and traditional enzyme inhibitors targeting PI3K and hypoxia inducible factor asparagine hydroxylase demonstrated highly effective inhibition of stem-like characteristics and tumor growth in hepatocellular carcinoma. [Hepatology] Abstract

Hypoxia-Inducible Gene 2 Promotes the Immune Escape of Hepatocellular Carcinoma from Nature Killer Cells through the Interleukin-10-STAT3 Signaling Pathway

Hypoxia-inducible gene 2 (HIG2) expression was upregulated in hepatocellular carcinoma (HCC). Silencing of HIG2 suppressed HCC cell migration and invasion. The killing effect of natural killer (NK) cells on HCC cells was enhanced after HIG2 was silenced in HCC cells. Conditioned media from HIG2-silenced SMMC-7721 cells inhibited the phenotype and function of NK cells. [J Exp Clin Cancer Res] Full Article

The Hypoxia Conditioned Mesenchymal Stem Cells Promote Hepatocellular Carcinoma Progression through YAP Mediated Lipogenesis Reprogramming

The authors found that mesenchymal stem cells (MSCs) under hypoxia condition could promote proliferation of hepatocellular carcinoma (HCC) cell lines and tumor growth in xenograft model. Hypoxia increased cyclooxygenase 2 expression in MSC and promoted the secretion of prostaglandin E₂, which then activated yes-associated protein (YAP) in HCC cells and led to increased cell proliferation. [J Exp Clin Cancer Res] Full Article

M2 Macrophages Mediate Sorafenib Resistance by Secreting HGF in a Feed-Forward Manner in Hepatocellular Carcinoma

Researchers demonstrated M2, but not M1, macrophages not only promoted proliferation, colony formation and migration of hepatoma cells but also significantly conferred tumor resistance to sorafenib via sustaining tumor growth and metastasis by secreting hepatocyte growth factor (HGF). HGF activated HGF/c-Met, ERK1/2/MAPK and PI3K/AKT pathways in tumor cells. [Br J Cancer] Full Article

Inhibition of eIF2α Dephosphorylation Accelerates Pterostilbene-Induced Cell Death in Human Hepatocellular Carcinoma Cells in an ER Stress and Autophagy-Dependent Manner

Mechanistic studies indicated that the combination of salubrinal and pterostilbene modulated endoplasmic reticulum (ER) stress-related autophagy through the phospho-eukaryotic initiation factor 2α/activating transcription factor-4/LC3 pathway, leading to a further inhibition of eIF2α dephosphorylation and the potentiation of cell death. [Cell Death Dis] Full Article

The HBx-CTTN Interaction Promotes Cell Proliferation and Migration of Hepatocellular Carcinoma via CREB1

A proteomics approach was used to identify hepatitis B virus-encoded X protein (HBx)-interacting proteins involved in HBx-induced hepatocarcinogenesis. Scientists validated the proteomics findings by co-immunoprecipitation and confocal microscopy. They performed cell proliferation, migration assays and cell cycle analyses in hepatocellular carcinoma cells. Finally, they confirmed the clinical significance of our findings in samples from patients. [Cell Death Dis] Full Article

Lgr5⁺ Stem/Progenitor Cells Reside at the Apex of a Heterogeneous Embryonic Hepatoblast Pool

Investigators showed that hepatoblasts were not only transcriptionally but also functionally heterogeneous, and that a sub-population of E9.5-E10.0 hepatoblasts exhibited a previously unidentified early-commitment to cholangiocyte fate. They also identified a sub-population constituting 2% of E9.5-E10.0 hepatoblasts that expressed the adult stem cell marker Lgr5, and generated both hepatocyte and cholangiocyte progeny that persisted for the life-span of the mouse. [Development] Abstract | Press Release

Extracellular Vesicles-Derived OncomiRs Mediate Communication between Cancer Cells and Cancer-Associated Hepatic Stellate Cells in Hepatocellular Carcinoma Microenvironment

Scientists found that the hepatocellular carcinoma (HCC) cells-released extracellular vesicles (EVs) contained more various OncomiRs which could activate hepatic stellate cells (HSCs) and transform them to cancer-associated HSCs (caHSCs), the caHSCs in turn exerted promotion effects on HCC cells through HSC-released EVs. [Carcinogenesis] Abstract

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Immune Cell Therapy for Hepatocellular Carcinoma

Effective immunotherapy combinations, such as the combination of checkpoint inhibitors and immune cell therapy, are needed. The authors focus on hepatocellular carcinoma among other solid tumors and discuss the current status and future of immune cell therapy in cancer immunotherapy. [J Hematol Oncol] Full Article

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Akero Therapeutics Initiates Phase IIa Clinical Trial of Investigational Therapy AKR-001 for the Treatment of NASH

Akero Therapeutics, Inc. announced that it has screened the first patient for its Phase IIa clinical trial evaluating AKR-001, the company’s lead product candidate for the treatment of non-alcoholic steatohepatitis (NASH). The FDA cleared the company’s Investigational New Drug application on May 24, 2019. [Akero Therapeutics, Inc.] Press Release

Metacrine Reports Positive Interim Results with Sustained FXR Agonist in NASH Patients

Metacrine, Inc. announced interim results from its Phase Ib clinical study of MET409 in ten patients with nonalcoholic steatohepatitis (NASH). MET409 dosed orally once-daily at 50 mg resulted in a 20% mean relative reduction in liver fat measured by MRI-PDFF and improved liver function tests after only four weeks of treatment. [Metacrine, Inc.] Press Release

Ambitious Open-Access Plan S Delayed to Let Research Community Adapt

A major push by some science agencies to make the research they fund open-access on publication — Plan S — has been delayed by a year. Funders now don’t have to start implementing the initiative until 2021, the agencies announced, to give researchers and publishers more time to adapt to the changes the bold plan requires. [Nature News] Editorial

No Paper, No PhD? India Rethinks Graduate Student Policy

PhD students in India will no longer be required to publish articles in academic journals before they are awarded their doctorates, if the country’s higher-education regulator adopts recommendations from a committee of researchers. [Nature News] Editorial

Bipartisan Bill Would Create Forum for Discussing How to Counter US Academic Espionage

Academic leaders say more dialogue is urgently needed on one issue now bedeviling the US research community: how to best protect the country against its economic and military competitors without choking off international scientific collaborations and the free flow of people and ideas. [ScienceInsider] Editorial

NEW Gordon Research Conference (GRC): Epigenomics of Diabetes and Other Metabolic Diseases
May 24-29, 2020
Hong Kong, China

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NEW Postdoctoral Position – Liver Disease (University of Illinois at Chicago)

Research Assistant – Liver Immunology (Maynooth University)

Postdoctoral Research Scientists – Hepatitis Virus Research (Ohio State University)

Faculty Position/Director – Cancer Research (Lewis Katz School of Medicine at Temple University)

Research Assistant – Liver Damage Research (University of Colorado Denver)

Tier I CIHR Canada Research Chair – Mechanisms of Health & Disease (Brock University)

Postdoctoral Fellow – Profiling Single Exosomes & Liver Metastasis Research (McGill University)

Research Scientist – Head of the Human Liver Cell Isolation Lab (University of California, San Diego)

Postdoctoral Researcher – Liver Mutagenesis (IRSET)

Postdoctoral Fellow – Fatty Liver Disease Research (Northeast Ohio Medical Universtiy)

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