Hepatic Cell News Volume 2.25 | Jul 6 2018

TOP STORY

Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma

Cabozantinib inhibits tyrosine kinases, including vascular endothelial growth factor receptors 1, 2, and 3, MET, and AXL, which are implicated in the progression of hepatocellular carcinoma and the development of resistance to sorafenib, the standard initial treatment for advanced disease. This randomized, double-blind, Phase III trial evaluated cabozantinib as compared with placebo in previously treated patients with advanced hepatocellular carcinoma. [N Engl J Med] Abstract | Press Release 1 | Press Release 2

(Ranked by impact factor of the journal)

Chronic Liver Injury Induces Conversion of Biliary Epithelial Cells into Hepatocytes

Researchers modeled human chronic liver injuries, without genetic manipulations, and assessed potential contributions of non-parenchymal cells to hepatocyte regeneration. [Cell Stem Cell] Abstract | Graphical Abstract

CTGF Mediates Tumor-Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression

Forced expression of connective tissue growth factor (CTGF) did not affect growth of PLC/PRF/5 cells, a hepatoma cell line with little CTGF expression, but facilitated their growth in the presence of LX-2 cells, a hepatic stellate cell line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by co-culture with LX-2 cells compared with monoculture. [Cancer Res] Abstract

PDSS2 Deficiency Induces Hepatocarcinogenesis by Decreasing Mitochondrial Respiration and Reprogramming Glucose Metabolism

Reintroduction of full-length prenyldiphosphate synthase subunit 2 (PDSS2) into hepatocellular carcinoma cells increased coenzyme Q10 and mitochondrial electron transport complex I activity and subsequently induced a metabolic shift from aerobic glycolysis to mitochondrial respiration in cells. Knockdown of PDSS2 induced chromosomal instability in the immortalized human liver cell line MIHA and induced malignant transformation. [Cancer Res] Abstract | Full Article

Prolonged Engraftment of Transplanted Hepatocytes in the Liver by Transient Pro-Survival Factor Supplementation Using Ex Vivo mRNA Transfection

To supply pro-survival protein only when it is needed, investigators used mRNA transfection, which exhibits transient protein expression profiles without the risk of genomic integration. Ex vivo transfection of mRNA encoding Bcl-2, a pro-survival factor, led to enhanced hepatocyte engraftment in both of normal and diseased mouse liver, effectively supporting liver function in a model of chronic hepatitis. [J Control Release] Abstract | Graphical Abstract

Novel ADAM-17 Inhibitor ZLDI-8 Enhances the In Vitro and In Vivo Chemotherapeutic Effects of Sorafenib on Hepatocellular Carcinoma Cells

Researchers demonstrated the discovery of a novel inhibitor for Notch activating/cleaving enzyme ADAM-17, named ZLDI-8; it inhibited the cleavage of NOTCH protein, consequently decreased the expression of pro-survival/anti-apoptosis and EMT related proteins. ZLDI-8 treatment enhanced the susceptibility of hepatocellular carcinoma cells to a small molecular kinase inhibitor Sorafenib, and chemotherapy agents Etoposide and Paclitaxel. [Cell Death Dis] Full Article

Epigenetic Silencing of Tumor Suppressor Gene CDKN1A by Oncogenic Long Non-Coding RNA SNHG1 in Cholangiocarcinoma

Scientists figured out that long non-coding RNA SNHG1, with substantially enhanced expression in cholangiocarcinoma (CCA), is capable of acting as the oncogenic molecule of CCA. They showed that SNHG1 bound to the histone methyltransferase enhancer of the zeste homolog 2, specifying the histone alteration pattern on the target genes, including CDKN1A, and, as a result, altered the CCA cell biology. [Cell Death Dis] Full Article

MicroRNA-500a Promotes the Progression of Hepatocellular Carcinoma by Post-Transcriptionally Targeting BID

Inhibition of miR-500a in hepatocellular carcinoma (HCC) cell lines significantly promoted apoptosis, as well as inhibited the proliferation of HCC cells and growth of transplanted tumors in nude mice. miR-500a directly targeted the 3′ untranslated region of BH3-interacting death agonist (BID) mRNA, and inhibition of miR-500a-promoted apoptosis was almost completely abolished by the administration of ABT-199 via the BID-mitochondria pathway. [Cell Physiol Biochem] Full Article

Knockout of Secretin Receptor Reduces Biliary Damage and Liver Fibrosis in Mdr2^−/− Mice by Diminishing Senescence of Cholangiocytes

Secretin receptor (SR), only expressed by cholangiocytes, plays a key role in the regulation of biliary damage and liver fibrosis. Investigators determined the effects of genetic depletion of SR in Mdr2^−/− mice on intrahepatic biliary mass, liver fibrosis, senescence, and angiogenesis. [Lab Invest] Abstract

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. Moreover, 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

TMUB1 Inhibits BRL-3A Hepatocyte Proliferation by Interfering with the Binding of CAML to Cyclophilin B through its TM1 Hydrophobic Domain

Co-immunoprecipitation assays in rat BRL-3A cells confirmed the interaction between transmembrane and ubiquitin-like domain-containing 1 (TMUB1) and calcium-modulating cyclophilin ligand (CAML); significant regulation of the influx of Ca²⁺ and hepatocyte proliferation occurred following TMUB1 overexpression or knockout. [Sci Rep] Full Article

Hepatocyte-Like Cells Generated by Direct Reprogramming from Murine Somatic Cells Can Repopulate Decellularized Livers

Researchers established a polycistronic expression system to induce the direct reprogramming of mouse embryonic fibroblasts towards hepatocytes. Hepatocyte‐like cells possessed the capacity to repopulate decellularized liver tissue and exhibited enhanced hepatic maturation. [Biotechnol Bioeng] Abstract

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Mechanisms of NAFLD Development and Therapeutic Strategies

Authors review the pathogenic and clinical features of nonalcoholic fatty liver disease (NAFLD), its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. [Nat Med] Abstract | Press Release

Visit our reviews page to see a complete list of reviews in the hepatic cell research field.

Abivax Releases Positive Top Line Data From ABX464-005 Phase IIa Study in HIV Infection

ABIVAX, a biotechnology company harnessing the immune system to develop a functional cure for HIV, as well as treatments for inflammatory/autoimmune diseases and cancer, announced positive top line data for the second cohort of the ABX464-005 phase IIa study in HIV infection. [ABIVAX] Press Release

Sanofi to further Accelerate its Scientific Presence with the Opening of a Global R&D Operations Hub in Chengdu, China

Sanofi is launching a Global R&D Operations Hub with a specialized focus on digitalization and big data analysis in Chengdu, Sichuan province, China. The new R&D operations hub confirms China as the third pillar of Sanofi Global Clinical Sciences and Operations, joining facilities in France and the United States. [Sanofi-Aventis U.S. LLC] Press Release

Controversial CRISPR ‘Gene Drives’ Tested in Mammals for the First Time

A controversial technology capable of altering the genomes of entire species has been applied to mammals for the first time. In a preprint posted to bioRxiv, researchers describe developing ‘gene drives’ — which could be used to eradicate problematic animal populations — in lab mice using the CRISPR gene-editing technique. [Nature News] Editorial

China’s Scientific Revolution

The country is making a serious investment in becoming a world-class science superpower. [Scientific American] Editorial

NEW Lorne Cancer Conference 2019
February 14-16, 2019
Lorne, Australia

Visit our events page to see a complete list of events in the community.

NEW Postdoctoral Position – Necroptosis in Liver Diseases (Irset – Research Institute for Environmental and Occupational Health)

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)

Postdoctoral Research Fellow – Gene Regulatory Mechanisms (University of California, Berkeley)

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

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

Postdoctoral Scholar – Cancer Biology (Penn State College of Medicine)

Postdoctoral Position – Necroptosis in Liver Diseases (Inserm)

EBPOD Fellowship – NAFLD/NASH (European Molecular Biology Laboratory)

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

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