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The Epstein-Barr virus encoded BART miRNAs potentiate tumor growth in vivo.

Qiu J, Smith P, Leahy L, Thorley-Lawson DA - PLoS Pathog. (2015)

Bottom Line: No effect was seen on invasion or metastasis, and the growth promoting activity was not seen in vitro.In vivo tumor growth was not associated with the expression of specific BART miRNAs but with up regulation of all the BART miRNAs, consistent with previous observations that all the BART miRNAs are highly expressed in all of the EBV associated cancers.Based on these observations, we suggest that deregulated expression of the BART miRNAs potentiates tumor growth and represents a general mechanism behind EBV associated oncogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.

ABSTRACT
The human herpes virus Epstein-Barr virus (EBV) latently infects and drives the proliferation of B lymphocytes in vitro and is associated with several forms of lymphoma and carcinoma in vivo. The virus encodes ~30 miRNAs in the BART region, the function of most of which remains elusive. Here we have used a new mouse xenograft model of EBV driven carcinomagenesis to demonstrate that the BART miRNAs potentiate tumor growth and development in vivo. No effect was seen on invasion or metastasis, and the growth promoting activity was not seen in vitro. In vivo tumor growth was not associated with the expression of specific BART miRNAs but with up regulation of all the BART miRNAs, consistent with previous observations that all the BART miRNAs are highly expressed in all of the EBV associated cancers. Based on these observations, we suggest that deregulated expression of the BART miRNAs potentiates tumor growth and represents a general mechanism behind EBV associated oncogenesis.

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Related in: MedlinePlus

Mouse models of EBV positive carcinoma.Cells from the luciferase tagged NPC line C666–1 and GaCa line AGS-BX1 were injected into the nasopharyngeal epithelium of NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice and tumor growth regularly monitored. A. Vital scans demonstrating the growth of primary tumors and metastases for C666–1 NPC cells. B. Typical histology of metastases from C666–1 NPC cells. C. Vital scans demonstrating the growth of primary tumors and metastases for AGS-BX1 GaCa cells. D. Typical histology of metastases from AGS-BX1 GaCa cells.
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ppat.1004561.g001: Mouse models of EBV positive carcinoma.Cells from the luciferase tagged NPC line C666–1 and GaCa line AGS-BX1 were injected into the nasopharyngeal epithelium of NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice and tumor growth regularly monitored. A. Vital scans demonstrating the growth of primary tumors and metastases for C666–1 NPC cells. B. Typical histology of metastases from C666–1 NPC cells. C. Vital scans demonstrating the growth of primary tumors and metastases for AGS-BX1 GaCa cells. D. Typical histology of metastases from AGS-BX1 GaCa cells.

Mentions: Fig. 1A and B show examples of C666–1 derived tumors grown in the NSG mouse model. The miRNA profiles of the cell lines before, during and after growth as tumors are shown in Fig. 2A. We did not observe specific changes in individual miRNAs rather all of the BART miRNAs were significantly up regulated when the cells grew as tumors in vivo compared to the parental lines (p<0.001). When the tumors were explanted for culture in vitro to become cell lines, the miRNA expression declined again to that of the parental line. However, this decline was fully reversible since upon reinjection back into the mice, the miRNA level again increased. In all, this process was reiterated three times with the same result, up regulation in vivo and down regulation in vitro (not shown). This suggests that increased expression of the BART miRNAs may confer a growth advantage to the tumor cells in vivo. Two of the three BHRF1 miRNAs also showed elevated copy numbers in the tumors although their expression levels were modest when compared to the BART miRNAs (not shown).


The Epstein-Barr virus encoded BART miRNAs potentiate tumor growth in vivo.

Qiu J, Smith P, Leahy L, Thorley-Lawson DA - PLoS Pathog. (2015)

Mouse models of EBV positive carcinoma.Cells from the luciferase tagged NPC line C666–1 and GaCa line AGS-BX1 were injected into the nasopharyngeal epithelium of NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice and tumor growth regularly monitored. A. Vital scans demonstrating the growth of primary tumors and metastases for C666–1 NPC cells. B. Typical histology of metastases from C666–1 NPC cells. C. Vital scans demonstrating the growth of primary tumors and metastases for AGS-BX1 GaCa cells. D. Typical histology of metastases from AGS-BX1 GaCa cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4295875&req=5

ppat.1004561.g001: Mouse models of EBV positive carcinoma.Cells from the luciferase tagged NPC line C666–1 and GaCa line AGS-BX1 were injected into the nasopharyngeal epithelium of NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice and tumor growth regularly monitored. A. Vital scans demonstrating the growth of primary tumors and metastases for C666–1 NPC cells. B. Typical histology of metastases from C666–1 NPC cells. C. Vital scans demonstrating the growth of primary tumors and metastases for AGS-BX1 GaCa cells. D. Typical histology of metastases from AGS-BX1 GaCa cells.
Mentions: Fig. 1A and B show examples of C666–1 derived tumors grown in the NSG mouse model. The miRNA profiles of the cell lines before, during and after growth as tumors are shown in Fig. 2A. We did not observe specific changes in individual miRNAs rather all of the BART miRNAs were significantly up regulated when the cells grew as tumors in vivo compared to the parental lines (p<0.001). When the tumors were explanted for culture in vitro to become cell lines, the miRNA expression declined again to that of the parental line. However, this decline was fully reversible since upon reinjection back into the mice, the miRNA level again increased. In all, this process was reiterated three times with the same result, up regulation in vivo and down regulation in vitro (not shown). This suggests that increased expression of the BART miRNAs may confer a growth advantage to the tumor cells in vivo. Two of the three BHRF1 miRNAs also showed elevated copy numbers in the tumors although their expression levels were modest when compared to the BART miRNAs (not shown).

Bottom Line: No effect was seen on invasion or metastasis, and the growth promoting activity was not seen in vitro.In vivo tumor growth was not associated with the expression of specific BART miRNAs but with up regulation of all the BART miRNAs, consistent with previous observations that all the BART miRNAs are highly expressed in all of the EBV associated cancers.Based on these observations, we suggest that deregulated expression of the BART miRNAs potentiates tumor growth and represents a general mechanism behind EBV associated oncogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.

ABSTRACT
The human herpes virus Epstein-Barr virus (EBV) latently infects and drives the proliferation of B lymphocytes in vitro and is associated with several forms of lymphoma and carcinoma in vivo. The virus encodes ~30 miRNAs in the BART region, the function of most of which remains elusive. Here we have used a new mouse xenograft model of EBV driven carcinomagenesis to demonstrate that the BART miRNAs potentiate tumor growth and development in vivo. No effect was seen on invasion or metastasis, and the growth promoting activity was not seen in vitro. In vivo tumor growth was not associated with the expression of specific BART miRNAs but with up regulation of all the BART miRNAs, consistent with previous observations that all the BART miRNAs are highly expressed in all of the EBV associated cancers. Based on these observations, we suggest that deregulated expression of the BART miRNAs potentiates tumor growth and represents a general mechanism behind EBV associated oncogenesis.

Show MeSH
Related in: MedlinePlus