Hepatic Cell News Volume 2.27 | Jul 20 2018

TOP STORY

Phospho-ERK is a Biomarker of Response to a Synthetic Lethal Drug Combination of Sorafenib and MEK Inhibition in Liver Cancer

To investigate the cause of the limited therapeutic effect of sorafenib, investigators performed a CRISPR-Cas9 based synthetic lethality screen to search for kinases whose knockout synergize with sorafenib. Drugs inhibiting the MEK or ERK kinases reversed unresponsiveness to sorafenib in vitro and in vivo in a subset of liver cancer cell lines characterized by high levels of active p-ERK through synergistic inhibition of ERK kinase activity. [J Hepatol] Abstract | Graphical Abstract

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A Novel TGF-β and H19 Signaling Axis in Tumor-Initiating Hepatocytes that Regulates Hepatic Carcinogenesis

RNA-seq analysis identified H19 as one of the most upregulated long noncoding RNA in association with Tgfbr2 inactivation in tumor-initiating hepatocytes (TICs). Researchers observed that forced overexpression of Sox2 in TICs increased the transcription of H19, whereas knockdown of Sox2 decreased it. Depletion of H19 reduced the progenitor property of TICs in vitro and decreased their tumorigenic potential in vivo. [Hepatology] Abstract

Dual Targeting of Histone Methyltransferase G9a and DNA-Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma

Scientists found a significant and correlative overexpression of G9a, DNMT1 and UHRF1 in hepatocellular carcinomas (HCCs) in association with poor prognosis. Independent G9a and DNMT1 pharmacological targeting synergistically inhibited HCC cell growth. [Hepatology] Abstract

Optimal Hypoxia Regulates Human iPSC-Derived Liver Bud Differentiation through Intercellular TGFB Signaling

Using a human induced pluripotent stem cell (hiPSC)-derived liver bud model, investigators found hypoxia induced with an O₂-permeable plate promoted hepatic differentiation accompanied by TGFB1 and TGFB3 suppression. Conversely, extensive hypoxia generated with an O₂-non-permeable plate elevated TGFBs and cholangiocyte marker expression. [Stem Cell Reports] Full Article

Design and Fabrication of a Liver-on-a-Chip Platform for Convenient, Highly Efficient, and Safe In Situ Perfusion Culture of 3D Hepatic Spheroids

Investigators developed a biomimetic and reversibly assembled liver-on-a-chip (3D-LOC) platform and presented a proof of concept for long-term perfusion culture of 3D human HepG2/C3A spheroids for building a 3D liver spheroid model. The polarisation, liver-specific functions, and metabolic activity of the cell spheroids in 3D-LOC were remarkably improved and exhibited better long-term maintenance over conventional perfusion methods. [Lab Chip] Abstract | Graphical Abstract

Zinc Alpha2 Glycoprotein Protects against Obesity-Induced Hepatic Steatosis

Zinc alpha2 glycoprotein (ZAG) expression was decreased in nonalcoholic fatty liver disease patient liver biopsy samples, obese mice livers, and palmitate-treated hepatocytes. ZAG significantly inhibited NF-ĸB/JNK signaling, resulting in suppression of obesity-associated inflammatory response in hepatocytes. [Int J Obes] Abstract

Crosstalk between Hepatic Tumor Cells and Macrophages via Wnt/β-Catenin Signaling Promotes M2-Like Macrophage Polarization and Reinforces Tumor Malignant Behaviors

Knockdown of β-catenin in M2 macrophages exhibited stronger antitumor characteristics when cocultured with Hepa1-6 hepatocellular carcinoma (HCC) cells in a series of experiments. Activation of Wnt signaling promoted M2 macrophage polarization through c-Myc. Co-culturing naïve macrophages with Hepa1-6 HCC cells in which Wnt ligands secretion was blocked by knockdown of Wntless inhibited M2 polarization in vitro. [Cell Death Dis] Full Article

Fibronectin Type III Domain-Containing 5 Attenuates Liver Fibrosis via Inhibition of Hepatic Stellate Cell Activation

Fibronectin type III domain-containing 5 (FNDC5) deficiency aggravated the high fat diet-induced liver fibrosis and hepatic stellate cells (HSCs) activation in mice. Administration of FNDC5 attenuated oxidized low density lipoprotein-induced AMPK deactivation, HSCs activation, connective tissue growth factor and transforming growth factor-β upregulation and extracellular matrix deposition in mouse HSCs. [Cell Physiol Biochem] Full Article

The Small Molecule Drug Diminazene Aceturate Inhibits Liver Injury and Biliary Fibrosis in Mice

Diminazene aceturate (DIZE) treatment, both in vivo and in vitro, markedly inhibited the activation of fibroblastic stellate cells which was associated with a reduced activation of Kupffer cells. DIZE-inhibited NOX enzyme assembly and ROS generation, activation of profibrotic transcription factors including p38, Erk1/2 and Smad2/3 proteins and proinflammatory and profibrotic cytokine release. [Sci Rep] Full Article

Novel 2-Phenyloxypyrimidine Derivative Induces Apoptosis and Autophagy via Inhibiting PI3K Pathway and Activating MAPK/ERK Signaling in Hepatocellular Carcinoma Cells

Given that the aberrant expression and activity of platelet-derived growth factor receptor α (PDGFRα) are closely associated with the pathogenesis of hepatocellular carcinoma, scientists present the discovery and identification of a novel PDGFRα inhibitor, N-(3-((4-(benzofuran-2-yl)pyrimidin-2-yl)oxy)-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide (E5) after comparison of different derivatives. They found that E5 inhibited proliferation and induced apoptosis in HCC cells. [Sci Rep] Full Article

Artificial microRNA Mediated Tgfbr2 and Pdgfrb Co-Silencing Ameliorates CCl4-Induced Hepatic Fibrosis in Mice

Investigators provide a proof-of-concept for the use of artificial microRNAs (amiRNAs)-mediated co-silencing of two profibrogenic pathways in liver fibrosis treatment, and highlight therapeutic potential of concatenated amiRNAs in gene therapy. They showed that amiRNA-mediated Pdgfrβ and Tgfbr2 co-silencing inhibited hepatic stellate cell activation and proliferation. [Hum Gene Ther] Abstract

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Serum Biomarkers for Diagnosis and Monitoring Viral Hepatitis and Hepatocellular Carcinoma

Chronic liver disease due to viral hepatitis continues to be a major global health concern. Timely diagnosis and treatment will prevent cirrhosis, risk of hepatocellular carcinoma, and requirement for liver transplantation. The authors summarize the established and emerging serological markers for diagnosis and managing viral hepatitis. [Expert Rev Mol Diagn] Abstract

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Poxel Announces Favorable Results for PXL770 Phase Ib Multiple Ascending Dose Trial and Drug-Drug Interaction Study

POXEL SA announced favorable results from the PXL770 Phase Ib two-part study that included a multiple ascending dose trial and a drug-drug interaction study. PXL770 is a first-in-class, oral, direct adenosine monophosphate-activated protein kinase activator that is advancing into a Phase IIa proof-of-concept program for the treatment of non-alcoholic steatohepatitis. [Poxel SA] Press Release

Blade Therapeutics Announces Initiation of Phase I Study of Lead Calpain Inhibitor BLD-2660 for Fibrosis

Blade Therapeutics, a biopharmaceutical company advancing novel anti-fibrotic therapies, announced the initiation of a Phase I clinical trial for its lead compound, BLD-2660. [Blade Therapeutics] Press Release

FDA Grants Breakthrough Therapy Designation for Genentech’s TECENTRIQ in Combination With Avastin as First-Line Treatment for Advanced or Metastatic Hepatocellular Carcinoma (HCC)

Genentech announced that the FDA has granted Breakthrough Therapy Designation for TECENTRIQ^® (atezolizumab) in combination with Avastin^® (bevacizumab) as an initial (first-line) treatment for people with advanced or metastatic HCC, the most common form of liver cancer. The designation is based on data from a Phase Ib study assessing the safety and clinical activity of the combination of TECENTRIQ and Avastin. [Genentech, Inc.] Press Release

Philippines Sweetens Deal for Scientists Who Return Home

A renewed government effort to draw Filipino scientists back to the Philippines by paying them to set up their own research labs or teach has met with a mixed reception. [Nature News] Editorial

Online Portal of Thousands of Clinical Trials Could Aid Disease Research

Under pressure to be more transparent about the results of drug testing studies, some companies have begun to share anonymized patient data from clinical trials with approved researchers on secure websites. An online platform aims to expand such efforts by offering a one-stop clearinghouse for those seeking to mine these data for new insights. [ScienceInsider] Editorial

Dutch Publishing Giant Cuts Off Researchers in Germany and Sweden

Elsevier stopped thousands of scientists in Germany from reading its recent journal articles, as a row escalates over the cost of a nationwide open-access agreement. The move comes just two weeks after researchers in Sweden lost access to the most recent Elsevier research papers, when negotiations on its contract broke down over the same issue. [Nature News] Editorial

New Policy Aims to Free Scientists to Focus on Research, Avoid Jumping through Hoops

Chinese scientific researchers are to be evaluated on the valuable contributions they make to their field rather than their number of published papers or academic credentials, according to a new policy issued by China’s top officials. The new policy is considered by experts to be the first volley of China’s resistance to efforts by the U.S. to suppress its high-tech development. [Chinanews.com] Editorial

NEW EASL Basic School of Hepatology: Liver Cell Isolation and Characterisation
January 16-18, 2019
Düsseldorf, Germany

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NEW Postdoctoral Position – High-Throughput Functional Screening of iPSC-Derived Models (KU Leuven)

NEW Postdoctoral Fellow – Computational Approaches to Prioritize Drugs and Drug Targets for Cancer Therapeutics (European Molecular Biology Laboratory)

Postdoctoral Position – Liver Cancer Translational Research (IDIBAPS)

Postdoctoral Positions – Medicinal Chemistry, Cellular and Experimental Biology and Systems Biology (University of Gothenburg)

Postdoctoral Fellows – Translational Oncology (Baylor College of Medicine)

Postdoctoral Fellow – Liver Cancer (Loyola University Chicago)

Group Leader – Systems Biology (Center for Systems Biology Dresden)

Postdoctoral/Project Leader – Hepatitis B and D Virus Research (University of Strasbourg)

Postdoctoral Position – Necroptosis in Liver Diseases (Inserm)

Postdoctoral Position – Inflammation and Metabolism (Sanford Burnham Prebys Medical Discovery Institute)

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