Gene Expression 17(2) Abstracts

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Gene Expression, Vol. 17, pp. 89-98, 2017
1052-2166/17 $90.00
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DOI: https://doi.org/10.3727/105221616X
693594
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


Differential Expression of MicroRNAs in Hepatitis C Virus-Mediated Liver Disease Between African Americans and Caucasians: Implications for Racial Health Disparities

Pradip B. Devhare,* Robert Steele,* Adrian M. Di Bisceglie,†‡ David E. Kaplan,§ and Ratna B. Ray*†‡

*Department of Pathology, Saint Louis University, St. Louis, MO, USA
†Department of Internal Medicine, Saint Louis University, St. Louis, MO, USA
‡Saint Louis University Liver Center, Saint Louis University, St. Louis, MO, USA
§Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

African Americans (AAs) have higher hepatocellular carcinoma (HCC) mortality rates than Caucasian Americans (CAs). Chronic hepatitis C virus (HCV) infection leads to cirrhosis and HCC. HCV infection is highly prevalent in the AA population compared to other racial groups. AAs are also less likely to naturally clear HCV, potentially contributing to higher prevalence of HCV. However, the explanation for this disparity is currently unknown. Circulating microRNAs (miRNAs) in the blood are emerging as biomarkers for pathological conditions. Expression analysis of miRNAs in major racial groups would be important for optimizing personalized treatment strategies. Here we assessed the differential expression of circulatory miRNAs from HCV-infected AA and CA patients. We identified increased expression of miR-146a, miR-150, and miR-155 in HCV-infected AA patient sera compared to that of CA. Further analysis demonstrated that these miRNAs were significantly elevated in AA patients diagnosed with HCV-mediated HCC. Higher expression of miR-150 was also noted in cirrhosis and HCC in AA patients, which may serve as a predictor of liver disease progression in this population. The differential expression of miRNAs suggests that these miRNAs and their target genes could be useful to gain further mechanistic insight of racial disparity associated with HCV-mediated pathogenesis.

Key words: Hepatitis C virus (HCV); Hepatocellular carcinoma (HCC); MicroRNAs (miRNAs); African Americans; Caucasian Americans

Address correspondence to Ratna B. Ray, Department of Pathology, Saint Louis University, DRC 207, 1100 South Grand Boulevard, St. Louis, MO 63104, USA. Tel: 314-977-7822; Fax: 314-771-3816; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 99-114, 2017
1052-2166/17 $90.00
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DOI: https://doi.org/10.3727/105221616X
693891
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


Knockdown of miR-23, miR-27, and miR-24 Alters Fetal Liver Development and Blocks Fibrosis in Mice

Charles E. Rogler, Joe S. Matarlo, Brian Kosmyna, Daniel Fulop, and Leslie E. Rogler

Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA

MicroRNAs (miRNAs) regulate cell fate selection and cellular differentiation. miRNAs of the miR23b polycistron (miR-23b, miR-27b, and miR-24) target components of the TGF-β signaling pathway and affect murine bile ductular and hepatocyte cell fate selection in vitro. Here we show that miR-23b polycistron miRNAs directly target murine Smad4, which is required for TGF-β signaling. Injection of antagomirs against these miRNAs directly into E16.5 murine fetuses caused increased cytokeratin expression in sinusoids and primitive ductular elements throughout the parenchyma of newborn mice. Similar antagomir injection in newborn mice increased bile ductular differentiation in the liver periphery and reduced hepatocyte proliferation. Antagomir injection in newborn Alb/TGF-β1 transgenic mice that develop fibrosis inhibited the development of fibrosis, and injection of older mice caused the resolution of existing fibrosis. Furthermore, murine stellate cell activation, including ColA1 and ACTA2 expression, is regulated by miR-23b cluster miRNAs. In summary, knockdown of miR-23b cluster miRNAs in fetal and newborn liver promotes bile duct differentiation and can block or revert TGF-β-induced liver fibrosis that is dependent on stellate cell activation. These data may find practical application in the highly needed development of therapies for the treatment of fibrosis.

Key words: Alb/TGF-β1; MicroRNA; miR-23; miR-27; miR-24; Liver; Liver fibrosis; Cell fate; Differentiation; Hepatic progenitors

Address correspondence to Leslie E. Rogler, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. Tel: 718-430-3651; Fax: 718-430-8975; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 115-127, 2017
1052-2166/17 $90.00
+ .00
DOI: https://doi.org/10.3727/105221616X
692991
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


Bile Duct Ligation Induces ATZ Globule Clearance in a Mouse Model of α-1 Antitrypsin Deficiency

Zahida Khan,*†‡ Shinichiro Yokota,§¶ Yoshihiro Ono,§ Aaron W. Bell,† Michael Oertel,† Donna B. Stolz,‡# and George K. Michalopoulos†‡

*Department of Pediatrics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
†Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
‡McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
§Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
¶Department of Surgery, Jichi Medical University, Shimotsuke, Japan
#Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

α-1 Antitrypsin deficiency (A1ATD) can progress to cirrhosis and hepatocellular carcinoma; however, not all patients are susceptible to severe liver disease. In A1ATD, a toxic gain-of-function mutation generates insoluble ATZ “globules” in hepatocytes, overwhelming protein clearance mechanisms. The relationship between bile acids and hepatocytic autophagy is less clear but may involve altered gene expression pathways. Based on previous findings that bile duct ligation (BDL) induces autophagy, we hypothesized that retained bile acids may have hepatoprotective effects in PiZZ transgenic mice, which model A1ATD. We performed BDL and partial BDL (pBDL) in PiZZ mice, followed by analysis of liver tissues. PiZZ liver subjected to BDL showed up to 50% clearance of ATZ globules, with increased expression of autophagy proteins. Analysis of transcription factors revealed significant changes. Surprisingly nuclear TFEB, a master regulator of autophagy, remained unchanged. pBDL confirmed that ATZ globule clearance was induced by localized stimuli rather than diet or systemic effects. Several genes involved in bile metabolism were overexpressed in globule-devoid hepatocytes, compared to globule-containing cells. Retained bile acids led to a dramatic reduction of ATZ globules, with enhanced hepatocyte regeneration and autophagy. These findings support investigation of synthetic bile acids as potential autophagy-enhancing agents.

Key words: Hepatocyte; Autophagy; PiZZ; Cholestasis; Liver regeneration

Address correspondence to Zahida Khan, M.D., Ph.D., Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Faculty Pavilion 6th Floor, Pittsburgh, PA 15224-1334, USA. Tel: (412) 692-5180; Fax: (412) 692-7355; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 129-140, 2017
1052-2166/17 $90.00
+ .00
DOI: https://doi.org/10.3727/105221616X
693855
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


Sorafenib and 2-Deoxyglucose Synergistically Inhibit Proliferation of Both Sorafenib-Sensitive and -Resistant HCC Cells by Inhibiting ATP Production

Ryan Reyes,* Nissar A. Wani,* Kalpana Ghoshal,†‡ Samson T. Jacob,*‡ and Tasneem Motiwala§

*Department of Cancer Biology and Genetics, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
†Department of Pathology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
‡Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
§Department of Biomedical Informatics, Wexner Medical Center, The Ohio State University, Columbus, OH, USA

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. Sorafenib is the only first-line systemic drug for advanced HCC, but it has very limited survival benefits because patients treated with sorafenibeither suffer from side effects or show disease progression after initial response. Thus, there is an urgent need to develop novel strategies for first-line and second-line therapies. The association between sorafenib resistance and glycolysis prompted us to screen several drugs with known antiglycolytic activity to identify those that will sensitize cells to sorafenib. We demonstrate that the combination of glycolytic inhibitor 2-deoxyglucose (2DG) and sorafenib drastically inhibits viability of sorafenib-sensitive and -resistant cells. However, the combination of other antiglycolytic drugs like lonidamine, gossypol, 3-bromopyruvate, and imatinib with sorafenib does not show synergistic effect. Cell cycle analysis revealed that the combination of 2DG and sorafenib induced cell cycle arrest at G0/G1. Mechanistic investigation suggests that the cell cycle arrest is due to depletion of cellular ATP that activates AMP-activated protein kinase (AMPK), which, in turn, inhibits mammalian target of rapamycin (mTOR) to induce cell cycle arrest. This study provides strong evidence for the therapeutic potential of the combination of sorafenib and 2DG for HCC.

Key words: Hepatocellular carcinoma (HCC); Sorafenib; Resistance; Glycolysis; 2-Deoxyglucose (2DG)

Address correspondence to Tasneem Motiwala, Ph.D., M.P.H., Department of Biomedical Informatics, Wexner Medical Center, The Ohio State University, 1800 Cannon Drive, Columbus, OH 43210, USA. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Samson T. Jacob, Ph.D., Department of Cancer Biology and Genetics, Wexner Medical Center, The Ohio State University, 420 W. 12th Avenue #646, Columbus, OH 43210, USA. E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 141-154, 2017
1052-2166/17 $90.00
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DOI: https://doi.org/10.3727/105221616X
693639
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


Review

Novel Advances in Understanding of Molecular Pathogenesis of Hepatoblastoma: A Wnt/β-Catenin Perspective

Danielle Bell,*† Sarangarajan Ranganathan,†‡ Junyan Tao,†§ and Satdarshan P. Monga†§¶

*Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
†Pittsburgh Liver Research Center, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
‡Division of Pediatric Pathology, Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
§Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA
¶Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Hepatoblastoma is the most common pediatric liver malignancy, typically striking children within the first 3 years of their young lives. While advances in chemotherapy and newer surgical techniques have improved survival in patients with localized disease, unfortunately, for the 25% of patients with metastasis, the overall survival remains poor. These tumors, which are thought to arise from hepatic progenitors or hepatoblasts, hence the name hepatoblastoma, can be categorized by histological subtyping based on their level of cell differentiation. Genomic and histological analysis of human tumor samples has shown exon-3 deletions or missense mutations in gene coding for β-catenin, a downstream effector of the Wnt signaling pathway, in up to 90% of hepatoblastoma cases. The current article will review key aberrations in molecular pathways that are implicated in various subtypes of hepatoblastoma with an emphasis on Wntsignaling. It will also discuss cooperation among components of pathways such as β-catenin and Yes-associated protein in cancer development. Understanding the complex network of molecular signaling in oncogenesis will undoubtedly aid in the discovery of new therapeutics to help combat hepatoblastoma.

Key words: Wnt signaling; Liver development; Liver tumor; Pediatric; Yap

Address correspondence to Satdarshan (Paul) Monga, M.D., University of Pittsburgh School of Medicine, 200 Lothrop Street, S-422 BST, Pittsburgh, PA 15261, USA. Tel: (412) 648-9966; Fax: (412) 648-1916; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Gene Expression, Vol. 17, pp. 155-171, 2017
1052-2166/17 $90.00
+ .00
DOI: https://doi.org/10.3727/105221616X
692568
E-ISSN 1555-3884
Copyright © 2017 Cognizant Comm. Corp.
Printed in the USA. All rights reserved


Review

Regulators of Cholangiocyte Proliferation

Chad Hall,*†‡ Keisaku Sato,§ Nan Wu,§ Tianhao Zhou,§ Konstantina Kyritsi,§ Fanyin Meng,*§¶ Shannon Glaser,*§¶ and Gianfranco Alpini‡§¶

*Research, Central Texas Veterans Health Care System, Temple, TX, USA
†Baylor Scott & White Digestive Disease Research Center, Temple, TX, USA
‡Department of Surgery, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA
§Operational Funds, Baylor Scott & White, Temple, TX, USA
¶Department of Medicine, Baylor Scott & White and Texas A&M Health Science Center, Temple, TX, USA

Cholangiocytes, a small population of cells within the normal liver, have been the focus of a significant amount of research over the past two decades because of their involvement in cholangiopathies such as primary sclerosing cholangitis and primary biliary cholangitis. This article summarizes landmark studies in the field of cholangiocyte physiology and aims to provide an updated review of biliary pathogenesis. The historical approach of rodent extrahepatic bile duct ligation and the relatively recent utilization of transgenic mice have led to significant discoveries in cholangiocyte pathophysiology. Cholangiocyte physiology is a complex system based on heterogeneity within the biliary tree and a number of signaling pathways that serve to regulate bile composition. Studies have expanded the list of neuropeptides, neurotransmitters, and hormones that have been shown to be key regulators of proliferation and biliary damage. The peptide histamine and hormones, such as melatonin and angiotensin, angiotensin, as well as numerous sex hormones, have been implicated in cholangiocyte proliferation during cholestasis. Numerous pathways promote cholangiocyte proliferation during cholestasis, and there is growing evidence to suggest that cholangiocyte proliferation may promote hepatic fibrosis. These pathways may represent significant therapeutic potential for a subset of cholestatic liver diseases that currently lack effective therapies.

Key words: Biliary epithelium; Cholangiopathies; Cholestasis; Liver damage

Address correspondence to Gianfranco Alpini, Ph.D., Central Texas Veterans Health Care System, Texas A&M Health Science Center College of Medicine, Olin E. Teague Medical Center, 1901 South 1st Street, Building 205, 1R60, Temple, TX 76504, USA. Tel: 254-743-2625, 254-743-1044; Fax: 254-743-0378, 254-743-0555; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it