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Liu, Bowen (2010) INVESTIGATION OF THE ROLE OF GLYPICAN 3 IN LIVER REGENERATION AND HEPATOCYTE PROLIFERATION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Glypican 3 (GPC3) belongs to a family of glycosylphosphatidylinositol-anchored, cell-surface heparan sulfate proteoglycans. The GPC3 gene is located on the X chromosome, and is highly expressed during embryogenesis and organogenesis. Loss-of-function mutations of GPC3 in humans result in the Simpson-Golabi-Behmel syndrome, an X-linked disorder characterized by pre- and post-natal liver and other organ overgrowth. GPC3 is one of the most over-expressed proteins in human hepatocellular carcinoma and is used as a novel diagnostic marker. However, its role in normal liver regeneration is still not well characterized. In this study, we investigated the role and effects of GPC3 in hepatocyte proliferation and liver regeneration, using 2/3 partial hepatectomy (PHx) model in rats and hepatocyte-targeted GPC3 transgenic mice. We found in rats that GPC3 mRNA and protein increase in a time frame which coincides with the termination of proliferative activities of either hepatocytes (day 2 after PHx and day 8-12 in culture) or non-parenchymal cells (day 5-6 after PHx). Blocking GPC3 expression using morpholino oligonucleotides promoted rat hepatocyte growth in vitro. We further generated GPC3 transgenic mice with hepatocyte-targeted over-expression of GPC3. These transgenic mice develop normally compared with their non-transgenic littermates, but have a suppressed rate of hepatocyte proliferation and liver regeneration after 2/3 PHx. Therefore we hypothesize that GPC3 is a negative regulator of hepatocyte proliferation and liver regeneration. The yeast two-hybrid assay revealed that GPC3 interacts with several interesting proteins including CD81, a cell membrane tetraspanin. CD81 levels changed in the same manner as GPC3 after rat PHx, and their interaction was confirmed by co-immunoprecipitation and co-immunofluorescence. The co-localization of GPC3 and CD81 after PHx indicates an important regulator interaction between the two proteins. Moreover, gene array analysis revealed a series of changes in the expression profiles in GPC3 transgenic mice. After PHx, a panel of cell cycle related genes and some oncogenes are either up- or down-regulated, which was confirmed by western blotting. Our results indicate that GPC3 plays a negative regulatory role in hepatocyte proliferation and liver regeneration in rats and hepatocyte-targeted transgenic mice, in which several potential proteins and multiple pathways are involved and affected.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Liu, Bowenbol9@pitt.eduBOL9
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairMars, Wendy Mwmars@pitt.eduWMARS
Committee MemberWu, Chuanyuecarywu@pitt.eduCARYWU
Committee MemberMichalopoulos, George Kmichalopoulosgk@upmc.eduMICHAL
Committee MemberFunderburgh, James Ljlfunder@pitt.eduJLFUNDER
Committee MemberLuo, Jian-hualuoj@upmc.eduLUOJH
Monga, Satdarshan P. Singhsmonga@pitt.eduSMONGA
Date: 13 August 2010
Date Type: Completion
Defense Date: 13 August 2010
Approval Date: 13 August 2010
Submission Date: 30 July 2010
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Hepatocyte proliferation; Liver regeneration; Partial hepatectomy; Glypican 3; Transgenic mouse
Other ID:, etd-07302010-140531
Date Deposited: 10 Nov 2011 19:55
Last Modified: 19 Dec 2016 14:36


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