Targeting beta-catenin in liver pathology: Novel Interactions, Novel Paradigms

Summary

Principal Investigator: SATDARSHAN SINGH MONGA
Abstract: DESCRIPTION (provided by applicant): Wnt/[unreadable]-catenin signaling is pertinent in liver biology in regulating zonation, regeneration, development and metabolism. However aberrations in this pathway have been reported in hepatic fibrosis, hepatic injury, hepatoblastomas and hepatocellular cancer (HCC). Targeting [unreadable] -catenin in HCC is imminent. It is the 3rd fatal cancer worldwide and its incidence and associated death rates have steadily increased since the 1980s. Cellular &molecular basis of HCC is poorly understood. Wnt signaling has been deemed active in 17-40% of HCCs due to various reasons and around 20-40% of all HCCs harbor monoallelic somatic mutations in the exon-3 of the [unreadable]-catenin gene (CTNNB1) that encodes for a non-serine/threonine phosphorylatable, stable and constitutively active protein, making it an attractive therapeutic target. We have made several important and some paradoxical observations over the last few years including identification of novel interactions and cross-regulations between [unreadable] -catenin and other molecules. These may have significant biological and translational implications mandating an in-depth analysis that may have widespread implications in not just HCC but other hepatic pathologies where [unreadable] -catenin targeting may be of essence such as hepatic fibrosis, injury and metabolic syndrome. The overarching hypothesis of the proposal is that therapeutic targeting of [unreadable] -catenin must take into account existing redundancies and crosstalk with specific signaling pathways, which need to be comprehensively elucidated. We will test these hypotheses in three distinct but thematically related aims. In aim 1, we will investigate the mechanism of oxidative stress dependent enhanced hepatocarcinogenesis in [unreadable] -catenin conditional knockout mice (Hep- [unreadable] -Cat KO) to address if enhanced HCC is a murine 'artifact'due to the role of - [unreadable] catenin in vitamin C biosynthesis in murine hepatocytes. We identified a novel role of [unreadable] -catenin signaling in vitamin C biosynthesis in the murine liver, whic is a known major antioxidant. Unlike humans and primates, rodents synthesize vitamin C in the hepatocytes and regular mouse chow is devoid of ascorbic acid. We hypothesize that increased HCC and oxidative stress in Hep- [unreadable] -Cat KO is due to compromised vitamin C biosynthesis and its normalization will alleviate HCC and demonstrate [unreadable] -catenin to be a global therapeutic target in HCC. In aim 2 we will investigate mechanism and biological implications of PDGFR[unreadable] upregulation and activation after [unreadable]-catenin inhibition in HCC cells. We hypothesize that PDGFR[unreadable] upregulation along with the activation of its specific downstream signaling arm is an important mechanism that will allow growth of HCC after [unreadable]-catenin inhibition and that understanding the role and regulation of this phenomena will bear significantly on efficacious HCC treatment. In aim 3, we will investigate the role and regulation of ?-catenin stabilization following inhibition of [unreadable]-catenin expression in the liver. We hypothesize that ?-catenin stabilization during [unreadable]-catenin inhibition in HCC will prevent any untoward effect related to disruption of cell-cell adhesion. All the proposed studies in the grant will utilize a balance of i vitro and in vivo set of experiments and the expected outcomes will be highly relevant and translational.
Funding Period: -----------------201 - ----------------2017
more information: NIH RePORT

Top Publications

  1. pmc β-Catenin signaling in hepatocellular cancer: Implications in inflammation, fibrosis, and proliferation
    Jung Min Lee
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Cancer Lett 343:90-7. 2014
  2. pmc Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent β-catenin activation in rodents
    Maura Fanti
    Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA Department of Biomedical Sciences, University of Cagliari, Italy
    Hepatology 59:2309-20. 2014
  3. pmc Hepatic regenerative medicine: exploiting the liver's will to live
    Satdarshan P S Monga
    Department of Pathology and Medicine, University of Pittsburgh, Pennsylvania Electronic address
    Am J Pathol 184:306-8. 2014
  4. ncbi β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation!
    Jing Yang
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
    Hepatology 60:964-76. 2014
  5. ncbi 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
    Gene Expr 16:51-62. 2014
  6. ncbi Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice
    Junyan Tao
    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California
    Gastroenterology 147:690-701. 2014

Detail Information

Publications6

  1. pmc β-Catenin signaling in hepatocellular cancer: Implications in inflammation, fibrosis, and proliferation
    Jung Min Lee
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
    Cancer Lett 343:90-7. 2014
    ..Also, β-catenin mutations and cirrhosis do not appear to cooperate in HCC pathogenesis in mice and men...
  2. pmc Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent β-catenin activation in rodents
    Maura Fanti
    Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA Department of Biomedical Sciences, University of Cagliari, Italy
    Hepatology 59:2309-20. 2014
    ..Administration of PKA inhibitor during T3 treatment of mice and rats as well as in cell culture abrogated Ser675-β-catenin and simultaneously decreased cyclin-D1 expression to block hepatocyte proliferation...
  3. pmc Hepatic regenerative medicine: exploiting the liver's will to live
    Satdarshan P S Monga
    Department of Pathology and Medicine, University of Pittsburgh, Pennsylvania Electronic address
    Am J Pathol 184:306-8. 2014
    ..This Guest Editorial introduces this month's special Liver Pathobiology Theme Issue, a series of reviews that encompass the discipline of hepatic regenerative medicine. ..
  4. ncbi β-catenin signaling in murine liver zonation and regeneration: a Wnt-Wnt situation!
    Jing Yang
    Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
    Hepatology 60:964-76. 2014
    ..Wls-LKO showed normal initiation of LR; however, Wls-MKO showed a significant but temporal deficit in LR that was associated with decreased β-catenin-TCF4 association and diminished Cyclin-D1 expression...
  5. ncbi 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
    Gene Expr 16:51-62. 2014
    ..In addition, the probability of therapeutically regulating β-catenin activity as a possible future treatment strategy for liver insufficiency will also be discussed. ..
  6. ncbi Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice
    Junyan Tao
    Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California
    Gastroenterology 147:690-701. 2014
    ..Yap functions as a transcriptional coactivator by interacting with TEA domain DNA binding proteins. We investigated the interactions among these pathways during hepatic tumorigenesis...

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. The Contribution of Activated Hepatic Stellate Cells to Hepatocarcinogenesis
    Dianne Helerie Dapito; Fiscal Year: 2013
    ..In summary, the three Aims of this proposal may establish the functional link between liver fibrosis and HCC, and are likely to point towards hepatic stellate cells as additional targets for HCC prevention or treatment.! ..
  3. Murine Model of HCV-Associated Human Liver Cancer
    Lishan Su; Fiscal Year: 2013
    ....
  4. Thioredoxin Inhibitory Protein in Chronic Liver Disease
    James Hamilton; Fiscal Year: 2013
    ..This mechanism will be evaluated directly, using bisulfite sequencing and methylation-specific PCR, as well as indirectly, using demethylating agents to reverse transcriptional silencing. ..
  5. Role of Platelet derived growth factor receptor-a in Liver Patho-biology
    SATDARSHAN SINGH MONGA; Fiscal Year: 2013
    ..Thus, this highly significant proposal will unequivocally and comprehensively address the role and regulation of PDGFR[unreadable] in liver health and disease. ..
  6. Mechanisms of oval cell activation and differentiation
    Bryon E Petersen; Fiscal Year: 2013
    ..This knowledge will help to guide the development of strategies for the therapeutic use of stem cell transplants for the treatment of liver disease. ..
  7. REGULATION AND FUNCTIONS OF METHIONINE ADENOSYLTRANSFERASE GENES IN LIVER
    SHELLY CHI LOO LU; Fiscal Year: 2013
    ....
  8. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  9. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
    ..abstract_text> ..
  10. Prevention of EtOH-induced promotion of hepatocarcinogenesis by genistein/soy
    Martin J J Ronis; Fiscal Year: 2013
    ....
  11. Role of Bone Marrow-Derived Myeloid Cells in Alcohol Liver Disease
    Cynthia Ju; Fiscal Year: 2013
    ..c) STAT3 activation and STAT1/NF-kB activation in BMMCs associated with mild ALD and ASH, respectively, will be investigated. ..
  12. Mechanisms and modifiers of beta-catenin-induced hepatic tumorigenesis
    KIMBERLEY JANE EVASON; Fiscal Year: 2013
    ..This project is relevant to cancer research and the missions of the NIH and NCI because it has the potential to reveal underlying mechanisms as well as potential therapeutic targets for HCC. ..
  13. Genetic models for exRNA communication
    Michael T McManus; Fiscal Year: 2013
    ..This U19 Cooperative Agreement directly addresses critical gaps in our knowledge of the fundamental principles of exRNA biogenesis, distribution, uptake, and function. ..
  14. INVESTIGATION OF THE ROLES OF NUCLEAR RECEPTOR FXR IN HEPATOCELLULAR
    Wendong Huang; Fiscal Year: 2013
    ..Results from these studies will not only provide insight into an etiological connection between liver metabolism and HCC but also help us develop novel approaches for the prevention and treatment of human HCC. ..
  15. DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITY
    Samuel Hawgood; Fiscal Year: 2013
    ..abstract_text> ..
  16. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  17. The role of Akt in cell survival and cell growth
    Nissim Hay; Fiscal Year: 2013
    ..Studies are also intended to delineate the role of this pathway in the development of hepatocellular carcinoma. ..
  18. Role of Uhrf1 in Liver Development, Regeneration and Carciogenesis
    Chinweike Ukomadu; Fiscal Year: 2013
    ..We believe that we have discovered a gene called UHRF1 that is involved in all the three processes and will study how it plays a role in each situation. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page ..
  19. Role of Bile Acids in the Initiation of Liver Regeneration
    Willscott E Naugler; Fiscal Year: 2013
    ....
  20. MECHANISMS OF LIVER INJURY BY HEPATITIS C AND ALCOHOL
    Steven A Weinman; Fiscal Year: 2013
    ....
  21. DYSREGULATION OF GSH SYNTHESIS DURING LIVER INJURY AND FIBROSIS
    SHELLY CHI LOO LU; Fiscal Year: 2013
    ....
  22. Role of microRNA-122 in hepatocarcinogenesis using conditional knock out mice
    Kalpana Ghoshal; Fiscal Year: 2013
    ..Thus, establishing role of miR-122 mimetic in an animal model (in preclinical trial) would be a major milestone in the treatment of this deadly disease in the near future. ..
  23. Role of inflammation in tumor promotion and progression
    Michael Karin; Fiscal Year: 2013
    ..We will investigate the mechanisms responsible for Sox9 expression in HPC, focusing on the role of the Notch pathway and will exploit Sox9 in lineage tracing experiments that will determine the origin of HPC. ..
  24. Omega-3 Fatty Acids and Hepatic Carcinogenesis
    Tong Wu; Fiscal Year: 2013
    ..Results from the proposed studies will provide important mechanistic insight and therapeutic implications for utilizing omega-3 PUFAs for the chemoprevention and treatment of human hepatocellular carcinoma. ..
  25. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  26. Molecular and Metabolic Pathology of CNC-bZIP Knockouts
    Jefferson Y Chan; Fiscal Year: 2013
    ..abstract_text> ..