Gene Expression 16(2) Abstracts

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Gene Expression, Vol. 16, pp. 51–62, 2014
1052-2166/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/105221614X13919976902138
E-ISSN 1555-3884
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Role and Regulation of β-Catenin Signaling During Physiological Liver Growth

Satdarshan (Paul) Singh Monga

Department of Pathology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Wnt/β-catenin signaling plays key roles not only during development but also in adult tissue homeostasis. This is also evident in liver biology where many temporal roles of β-catenin have been identified during hepatic development, where, in hepatic progenitors or hepatoblasts, it is a key determinant of proliferation and eventually differentiation to mature hepatocytes, while also playing an important role in bile duct homeostasis. β-Catenin signaling cascade is mostly quiescent in hepatocytes in an adult liver except in the centrizonal region of a hepatic lobule. This small rim of hepatocytes around the central vein show constitutive β-catenin activation that in turn regulates expression of genes whose products play an important role in ammonia and xenobiotic metabolism. Intriguingly, β-catenin can also undergo activation in hepatocytes after acute liver loss secondary to surgical or toxicant insult. Such activation of this progrowth protein is observed as nuclear translocation of β-catenin and formation of its complex with the T-cell factor (TCF) family of transcription factors. Expression of cyclin-D1, a key inducer of transition from the G1 to S phase of cell cycle, is regulated by β-catenin–TCF complex. Thus, β-catenin activation is absolutely critical in the normal regeneration process of the liver as shown by studies in several models across various species. In the current review, the temporal role and regulation of β-catenin in liver development, metabolic zonation in a basal adult liver, and during the liver regeneration process will be discussed. In addition, the probability of therapeutically regulating β-catenin activity as a possible future treatment strategy for liver insufficiency will also be discussed.

Key words: Liver development; Liver regeneration; Proliferation; Glutamine synthetase; Cyclin-D1; Nonparenchymal cells; Zonation

Address correspondence to Satdarshan Pal Singh Monga, M.D.,Vice Chair of Experimental Pathology, Endowed Chair of Experimental Pathology, Professor of Pathology and Medicine (Gastroenterology, Hepatology, and Nutrition), University of Pittsburgh School of Medicine, 200 Lothrop Street S-422 BST, Pittsburgh, PA 15261, USA. Tel: +1-412-648-9966; Fax: +1-412-648-1916; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 16, pp. 63–75, 2014
1052-2166/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/105221614X13919976902219
E-ISSN 1555-3884
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Med1 Subunit of the Mediator Complex in Nuclear Receptor-Regulated Energy Metabolism, Liver Regeneration, and Hepatocarcinogenesis

Yuzhi Jia,* Navin Viswakarma,† and Janardan K. Reddy*

*Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
†Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL, USA

Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARa-activating ligands, while others such as ACOX1 (fatty acyl- CoA oxidase1) inactivate these endogenous PPARa activators. In the absence of ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARa, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription. Evidence indicates that the Med1 subunit of the Mediator is essential for PPARa, PPARg, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARa activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic diseases associated with increased energy combustion in liver.

Key words: Liver regeneration; Mediator complex; Med1; Hepatocarcinogenesis

Address correspondence to Yuzhi Jia, Department of Pathology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA. Tel: +1-312-503-7948; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it or Navin Viswakarma, Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, IL 60153, USA. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 16, pp. 77–84, 2014
1052-2166/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/105221614X13919976902057
E-ISSN 1555-3884
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Hepatic Fibrosis and the Microenvironment: Fertile Soil for Hepatocellular Carcinoma Development

Michael C. Wallace*† and Scott L. Friedman*

*Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA
†School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia

Hepatocellular carcinoma is an emerging worldwide health threat that has few curative treatment options and poor overall survival. Progressive hepatic fibrosis is a common pathway for all forms of chronic liver disease and is closely linked epidemiologically to hepatocellular carcinoma risk. However, the molecular events that predispose a fibrotic liver to cancer development remain elusive. Nonetheless, a permissive hepatic microenvironment provides fertile soil for transition of damaged hepatocytes into hepatocellular carcinoma. Key predisposing features include alterations in the extracellular matrix, bidirectional signaling pathways between parenchymal and nonparenchymal cells, and immune dysfunction. Emerging research into the contributions of autophagy, tumor-associated fibroblasts, and hepatocellular carcinoma progenitor cells to this dangerous milieu also provides new mechanistic underpinnings to explain the contribution of fibrosis to cancer. As effective antifibrotic therapies are developed, these approaches could attenuate the rising surge of hepatocellular carcinoma associated with chronic liver disease.

Key words: Hepatocellular carcinoma (HCC); Liver fibrosis; Hepatic stellate cells (HSCs); Extracellular matrix (ECM)

Address correspondence to Scott L. Friedman, M.D., Division of Liver Diseases, Box 1123, Mount Sinai School of Medicine, 1425 Madison Ave., Room 11-70C, New York, NY 10029, USA. Fax: +1-212-849-2574; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 16, pp. 85–92, 2014
1052-2166/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/105221614X13919976902093
E-ISSN 1555-3884
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Regulation of Glucose Metabolism in Hepatocarcinogenesis by MicroRNAs

Ryan K. Reyes,*† Tasneem Motiwala,†‡ and Samson T. Jacob†‡

*Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA
†Department of Molecular and Cellular Biochemistry, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
‡Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

In the past decade, considerable effort has been made in elucidating the mechanism underlying the high level of aerobic glycolysis in cancer cells. While some recent studies have attempted to address this issue, the potential role of microRNAs in this process has not been explored until recently. These studies have demonstrated involvement of just five deregulated miRNAs in glucose metabolism in hepatocarcinogenesis. This review discusses the metabolic significance of these miRNAs in hepatoceullular carcinoma, their targets in glycolysis, gluconeogenesis, and pentose phosphate pathways, and provides an insight into the therapeutic potential of targeting specific miRNAs.

Key words: Hepatocellular carcinoma; Glucose metabolism; MicroRNA

Address correspondence to Samson T. Jacob, Ph.D. 646A Tzagournis Medical Research Facility, 420 W. 12th Ave, Columbus, OH 43210, USA. Tel: +1-614-688-5494; Fax: +1-614-688-5600; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 16, pp. 93–99, 2014
1052-2166/13 $90.00 + .00
DOI: http://dx.doi.org/10.3727/105221614X13919976902174
E-ISSN 1555-3884
Copyright © 2014 Cognizant Comm. Corp.
Printed in the USA. All rights reserved

Review

Emerging Insights Into the Role of MicroRNAs in the Pathogenesis of Cholangiocarcinoma

Hiroaki Haga, Irene Yan, Kenji Takahashi, Joseph Wood, and Tushar Patel

Mayo Clinic, Jacksonville, FL, USA

The microRNAs (miRNAs) are small noncoding RNAs that are potent regulators of gene expression and can regulate several diverse biological functions. This minireview provides an overview of recent studies that have examined the role and involvement of miRNAs in cholangiocarcinomas. These studies provide evidence for deregulated expression of miRNA and are providing new insights into the potential contribution of these in the pathogenesis of cholangiocarcinoma.

Key words: Biliary tract cancers; Noncoding RNA; Epithelial–mesenchymal transition; Cell proliferation; Cell death

Address correspondence to Tushar Patel, MBChB, AGAF, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. Tel: +1-904-956-3257; Fax: +1-904-956-3359; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it