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Targeted Deletion of Ptp4a3 Inhibits Colon Carcinogenesis and Angiogenesis

Zimmerman, Mark W (2013) Targeted Deletion of Ptp4a3 Inhibits Colon Carcinogenesis and Angiogenesis. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Protein tyrosine phosphatase 4a3 (Ptp4a3) is an enigmatic member of the Ptp4a family of prenylated protein tyrosine phosphatases, which are highly expressed in many human cancers. Despite strong correlations with tumor metastasis and poor patient prognosis, there is very limited understanding of this gene family’s role in malignancy. A gene targeted mouse knockout model for Ptp4a3, the most widely studied Ptp4a family member, was created. Mice deficient for PTP4A3 were grossly normal. However, fewer homozygous-null males were observed at weaning and they maintained a decreased body mass into adulthood.
Although PTP4A3 is normally associated with late-stage cancer and metastasis, increased Ptp4a3 mRNA was observed in the colon of C57BL/6J mice immediately following treatment with the carcinogen azoxymethane. A well characterized murine colitis-associated colon cancer model was used to investigate the role of PTP4A3 in malignancy. Wildtype mice treated with azoxymethane and dextran sodium sulfate (AOM/DSS) developed approximately 7-10 tumors per mouse in the distal colon. The resulting tumor tissue had 4-fold more Ptp4a3 mRNA relative to normal colon epithelium and increased PTP4A3 protein. Ptp4a3-null mice developed 50% fewer colon tumors than wildtype mice after exposure to AOM/DSS. Tumors from the Ptp4a3-null mice had elevated levels of both IGF1Rβ and c-MYC compared to tumors replete with PTP4A3, suggesting an enhanced cell signaling pathway engagement in the absence of the phosphatase. Furthermore, c-MYC activity was able to increase Ptp4a3 gene expression in a fibroblast cell culture model. These results provide the first definitive evidence implicating PTP4A3 in colon carcinogenesis and highlight the potential value of the phosphatase as a therapeutic target for early stage malignant disease.
Interestingly, PTP4A3 is also expressed in the tumor vasculature and has been proposed to be a direct target of vascular endothelial growth factor (VEGF) signaling in endothelial cells. Compared to wildtype controls, colon tumor tissue isolated from Ptp4a3-null mice revealed reduced microvessel density demonstrated by CD31 staining. Vascular cells derived from Ptp4a3-null tissue explants exhibited decreased invasiveness ex vivo compared to wildtype tissues. When primary endothelial cells were isolated and cultured in vitro, Ptp4a3-null cells displayed less migration compared to wildtype cells and loss of VEGF-induced phosphorylation of SRC protein. Reduced migration and SRC activation were also observed when human endothelial cells were treated with a small molecule inhibitor of PTP4A3. These findings strongly support a role for PTP4A3 as an important contributor to cancer progression as well as endothelial cell function in vivo.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zimmerman, Mark Wmwz2@pitt.eduMWZ2
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeFranco, Donald Bdod1@pitt.eduDOD1
Thesis AdvisorHomanics, Gregg Ehomanicsge@anes.upmc.eduGEH2
Thesis AdvisorLazo, John
Committee MemberSmithgall, Thomas Etsmithga@pitt.eduTSMITHGA
Committee MemberIsenberg, Jeff Sjsi5@pitt.eduJSI5
Committee MemberBahary, Nathanbahary@pitt.eduBAHARY
Date: 30 April 2013
Date Type: Publication
Defense Date: 15 April 2013
Approval Date: 30 April 2013
Submission Date: 30 April 2013
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 114
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Phosphatase, Cancer, Angiogenesis
Date Deposited: 30 Apr 2013 15:21
Last Modified: 19 Dec 2016 14:40


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