Hepatic Cell News Volume 3.23 | Jun 28 2019

TOP STORY

Type 3 Inositol 1,4, 5-Trisphosphate Receptor Is Increased and Enhances Malignant Properties in Cholangiocarcinoma

Type 3 inositol 1,4,5-trisphosphate receptor (ITPR3) expression was increased in both hilar and intrahepatic cholangiocarcinoma (CCA) samples as well as in CCA cell lines. Deletion of ITPR3 from CCA cells impaired proliferation and cell migration. A bioinformatic analysis suggested that over-expression of ITPR3 in CCA would have a mitochondrial phenotype, so this also was examined. [Hepatology] Abstract

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HIF-1α-Induced RIT1 Promotes Liver Cancer Growth and Metastasis and Its Deficiency Increases Sensitivity to Sorafenib

Scientists revealed that Ras-like-without-CAAX-1 (RIT1) functioned as an oncogene, as overexpression of RIT1 enhanced hepatocellular carcinoma cell proliferation and aggressive behavior, whereas silencing RIT1 expression repressed the malignant behaviors. Furthermore, RIT1 deficiency increased drug sensitivity to sorafenib treatment. [Cancer Lett] Abstract

The RNA-Binding Protein RBM3 Promotes Cell Proliferation in Hepatocellular Carcinoma by Regulating Circular RNA SCD-CircRNA 2 Production

Researchers observed that the production of stearoyl-CoA desaturase (SCD)-circRNA 2 was dynamically regulated by RNA-binding protein 3 (RBM3). By modulating RBM3 or SCD-circRNA 2 levels, they found that RBM3 promoted hepatocellular carcinoma cell proliferation in a SCD-circRNA 2 dependent manner. [EBioMedicine] Full Article

Hepatocyte PRMT1 Protects from Alcohol Induced Liver Injury by Modulating Oxidative Stress Responses

Investigators found that alcohol promoted protein arginine methyltransferase 1 (PRMT1) dephosphorylation at S297. Phosphorylation at this site was necessary for PRMT1-dependent protein arginine methylation. PRMT1 S297A, a dephosphorylation mimic of PRMT1 had reduced ability to promote gene expression of pro-inflammatory cytokines, pro-apoptotic genes BIM and TRAIL and expression of a suppressor of hepatocyte proliferation, Hnf4α. [Sci Rep] Full Article

MicroRNA-448 Inhibits Stemness Maintenance and Self-Renewal of Hepatocellular Carcinoma Stem Cells through the MAGEA6-Mediated AMPK Signaling Pathway

Scientists explored whether or not miR-448 and melanoma-associated antigen 6 (MAGEA6) were involved in the self-renewal and stemness maintenance of hepatocellular carcinoma stem cells. The interaction among miR-448, MAGEA6, and the AMPK signaling pathway was evaluated. [J Cell Physiol] Abstract

Altered FoxO1 and PPARγ Interaction in Age-Related ER Stress-Induced Hepatic Steatosis

The authors showed that forkhead box O1 (FoxO1)-induced hepatic lipid accumulation was negatively regulated by Akt signaling. PPARγ, a key lipogenesis transcription factor, was increased in aged liver, resulting in lipid accumulation via hepatic endoplasmic reticulum (ER) stress under hyperglycemic conditions. They further demonstrated that loss of FoxO1 caused a decline in PPARγ expression and reduced lipid accumulation. [Aging (Albany NY)] Abstract

A Liver-Specific LncRNA, FAM99B, Suppresses Hepatocellular Carcinoma Progression through Inhibition of Cell Proliferation, Migration, and Invasion

Investigators evaluated the expression of long non-coding RNAs (lncRNA) FAM99B and its biological function in hepatocellular carcinoma (HCC). HCCLM3 was transfected with lentivirus containing full-length FAM99B to obtain stable overexpressing cell line. Cell Counting Kit 8, clone formation, and transwell assays were used to investigate the effects of FAM99B in HCC progression. [J Cancer Res Clin Oncol] Abstract

Silencing of Long Noncoding RNA HOXD-AS1 Inhibits Proliferation, Cell Cycle Progression, Migration and Invasion of Hepatocellular Carcinoma Cells through MEK/ERK Pathway

In vitro loss-of-function experiments revealed that silencing of HOXD cluster antisense RNA 1 (HOXD-AS1) could dramatically suppress the proliferation, migration, and invasion, and induce S or/and G2/M phase cell cycle arrest as well as apoptosis of Bel-7402 and MHCC97H cells accompanying the changes in expression levels of cyclin B1, cyclin D1, BCL-2, BAX, and MMP2. [J Cell Biochem] Abstract

Pterostilbene Reverses Palmitic Acid Mediated Insulin Resistance in HepG2 Cells by Reducing Oxidative Stress and Triglyceride Accumulation

Researchers evaluated the ability of pterostilbene (PTS), a methoxylated analog of resveratrol and a known antioxidant, to reverse palmitic acid (PA)-mediated insulin resistance in HepG2 cells. PTS prevented ROS formation and subsequent oxidative lipid damage by reducing the expression of NADPH oxidase 3 in PA treated HepG2 cells. [Free Radic Res] Abstract

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The Role of Telomeres and Telomerase in Cirrhosis and Liver Cancer

An understanding of the role of telomeres and telomerase in hepatocellular carcinoma development is important to develop future targeted therapies and improve survival of this disease. In this review, the roles of telomeres and telomerase in liver carcinogenesis are discussed, in addition to their potential translation to clinical practice as biomarkers and therapeutic targets. [Nat Rev Gastroenterol Hepatol] Abstract

The Role of Senescence in the Development of Non-Alcoholic Fatty Liver Disease and Progression to Non-Alcoholic Steatohepatitis

The authors summarize the current literature on the impact of cellular senescence in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis, and discuss the effectiveness and safety of novel senolytic drugs and therapeutic options available to delay or treat the disease. They identify the open questions and issues to be addressed in the near future. [Hepatology] Abstract

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Terns Pharmaceuticals Announces Exclusive Licensing and Collaboration Agreement with GENFIT to Develop and Commercialize Elafibranor in the Greater China Region

Terns Pharmaceuticals, Inc. announced an exclusive licensing and collaboration agreement with GENFIT. Under the terms of the agreement, Terns acquires the exclusive right to develop, register, and market elafibranor for the treatment of non-alcoholic steatohepatitis and primary biliary cholangitis in Greater China. [Terns Pharmaceuticals, Inc.] Press Release

Bristol-Myers Squibb Announces Results from CheckMate -459 Study Evaluating Opdivo (Nivolumab) as a First-Line Treatment for Patients with Unresectable Hepatocellular Carcinoma

Bristol-Myers Squibb Company announced topline results from CheckMate -459, a randomized Phase III study evaluating Opdivo versus sorafenib as a first-line treatment in patients with unresectable hepatocellular carcinoma. The trial did not achieve statistical significance for its primary endpoint of overall survival per the pre-specified analysis. [Bristol-Myers Squibb Company] Press Release

Final Data Analysis of Phase II PBC Trial Shows that Genkyotex’s Anti-Fibrotic Candidate GKT831 Demonstrated Statistically Significant Improvements in GGT and ALP over Full Treatment Period

Genkyotex announced the final results of its Phase II trial of GKT831 in primary biliary cholangitis (PBC). These data include pre-determined secondary efficacy analyses that were not previously available, as well as full safety data. [Genkyotex] Press Release

Gemphire Announces Top-Line Data from Familial Partial Lipodystrophy (FPLD) Phase IIa Proof-of-Concept NAFLD/NASH Clinical Trial

Gemphire Therapeutics Inc. announced top-line results based upon the company’s preliminary review of the limited top-line dataset from the investigator-led Phase IIa study of adult FPLD patients evaluating efficacy, safety, and tolerability of oral gemcabene. [Gemphire Therapeutics Inc.] Press Release

Conatus Announces Results from ENCORE-LF and ENCORE-PH Phase IIb Clinical Trials in NASH Cirrhosis

Conatus Pharmaceuticals Inc. announced that top-line results from the company’s ENCORE-LF clinical trial of emricasan did not meet its primary endpoint and the company is discontinuing further treatment of patients enrolled in the ENCORE-LF clinical trial. [Conatus Pharmaceuticals Inc.] Press Release

Cara Therapeutics Announces Initiation of Phase II Trial of Oral KORSUVAᵀᴹ (CR845/Difelikefalin) for Pruritus in Patients with Primary Biliary Cholangitis (PBC)

Cara Therapeutics, Inc. announced the initiation of a Phase II trial of Oral KORSUVA for the treatment of pruritus in patients with hepatic impairment due to PBC. Pruritus is a common symptom of cholestatic liver diseases with a prevalence of up to 70 percent in patients with PBC. [Cara Therapeutics, Inc.] Press Release

Translate Bio Announces FDA Clearance to Proceed with a Single-Ascending Dose (SAD) Phase I/II Clinical Trial for Ornithine Transcarbamylase (OTC) Deficiency

Translate Bio announced that it has received clearance from the FDA to proceed with a SAD Phase I/II clinical trial of MRT5201 in adult patients with OTC deficiency. MRT5201 is designed to treat patients with OTC deficiency by intravenous delivery of mRNA encoding fully functional OTC enzyme to the liver to enable the hepatocytes to produce the normal OTC enzyme. [Translate Bio] Press Release

Arrowhead Pharmaceuticals Receives Fast Track Designation for ARO-AAT for Treatment of Alpha-1 Liver Disease

Arrowhead Pharmaceuticals Inc. announced that the FDA has granted Fast Track designation to ARO-AAT, the company’s second generation subcutaneously administered RNA interference therapeutic being developed as a treatment for a rare genetic liver disease associated with alpha-1 antitrypsin deficiency. [Arrowhead Pharmaceuticals Inc.] Press Release

Arcturus Therapeutics Receives Orphan Drug Designation from the US FDA for ARCT-810, for Treatment of Ornithine Transcarbamylase (OTC) Deficiency

Arcturus Therapeutics Holdings Inc. announced the FDA has granted Orphan Drug Designation for the company’s lead product candidate ARCT-810 to treat OTC deficiency. ARCT-810 utilizes Arcturus’ LUNAR^® lipid-mediated delivery platform to safely and effectively deliver OTC messenger RNA to liver cells. [Arcturus Therapeutics Holdings Inc.] Press Release

ContraVir Pharmaceuticals Submits IND Application for CRV431 for NASH

ContraVir Pharmaceuticals, Inc. announced the filing of an Investigational New Drug (IND) application with the FDA for CRV431 for the treatment of NASH. ContraVir’s proposed IND opening study is entitled, “An Open-Label Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics of CRV431.” [ContraVir Pharmaceuticals, Inc.] Press Release

NIH Probe of Foreign Ties Has Led to Undisclosed Firings—and Refunds from Institutions

An aggressive effort by the National Institutes of Health (NIH) to enforce rules requiring its grantees to report foreign ties is still gathering steam. But it has already had a major impact on the US biomedical research community. A senior NIH official tells ScienceInsider that universities have fired more scientists—and refunded more grant money—as a result of the effort than has been publicly known. [ScienceInsider] Editorial

Discrimination Drives LGBT+ Scientists to Think About Quitting

Nearly one-third of physical scientists from sexual and gender minorities in the United Kingdom have considered leaving their jobs because of their workplace climate, suggests a survey. And 18% who are lesbian, gay, bisexual, transgender or from other sexual and gender minorities (LGBT+) said they had experienced harassment, bullying or exclusionary behavior in the workplace. [Nature News] Editorial

NEW EMBL Conference: Cancer Genomics
November 4-6, 2019
Heidelberg, Germany

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

NEW Research Professor – Nutrition & Metabolic Diseases (KU Leuven)

Research Lab Specialist – Tumor Microenvironment & Cell Behavior (University of Southern California)

PhD Position – Cytokine-Induced Metabolic Rewiring of the Liver (Research Center for Molecular Medicine of the Austrian Academy of Sciences)

Postdoctoral Scientist – Epigenetic Mechanisms of NAFLD (Institute of Hepatology, Foundation for Liver Research)

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)

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