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Nuclear Factor kappa B is central to Marek's disease herpesvirus induced neoplastic transformation of CD30 expressing lymphocytes in-vivo.

Kumar S, Kunec D, Buza JJ, Chiang HI, Zhou H, Subramaniam S, Pendarvis K, Cheng HH, Burgess SC - BMC Syst Biol (2012)

Bottom Line: The exact mechanism of neoplastic transformation from CD30(lo) expressing phenotype to CD30(hi) expressing neoplastic phenotype is unknown.Here, using microarray, proteomics and Systems Biology modeling; we compare the global gene expression of CD30(lo) and CD30(hi) cells to identify key pathways of neoplastic transformation.We propose and test a specific mechanism of neoplastic transformation, and genetic resistance, involving the MDV oncogene Meq, host gene products of the Nuclear Factor Kappa B (NF-κB) family and CD30; we also identify a novel Meq protein interactome.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathobiology and Population Medicine, Mississippi State University, MS 39762, USA. skumar@cvm.msstate.edu

ABSTRACT

Background: Marek's Disease (MD) is a hyperproliferative, lymphomatous, neoplastic disease of chickens caused by the oncogenic Gallid herpesvirus type 2 (GaHV-2; MDV). Like several human lymphomas the neoplastic MD lymphoma cells overexpress the CD30 antigen (CD30(hi)) and are in minority, while the non-neoplastic cells (CD30(lo)) form the majority of population. MD is a unique natural in-vivo model of human CD30(hi) lymphomas with both natural CD30(hi) lymphomagenesis and spontaneous regression. The exact mechanism of neoplastic transformation from CD30(lo) expressing phenotype to CD30(hi) expressing neoplastic phenotype is unknown. Here, using microarray, proteomics and Systems Biology modeling; we compare the global gene expression of CD30(lo) and CD30(hi) cells to identify key pathways of neoplastic transformation. We propose and test a specific mechanism of neoplastic transformation, and genetic resistance, involving the MDV oncogene Meq, host gene products of the Nuclear Factor Kappa B (NF-κB) family and CD30; we also identify a novel Meq protein interactome.

Results: Our results show that a) CD30(lo) lymphocytes are pre-neoplastic precursors and not merely reactive lymphocytes; b) multiple transformation mechanisms exist and are potentially controlled by Meq; c) Meq can drive a feed-forward cycle that induces CD30 transcription, increases CD30 signaling which activates NF-κB, and, in turn, increases Meq transcription; d) Meq transcriptional repression or activation of the CD30 promoter generally correlates with polymorphisms in the CD30 promoter distinguishing MD-lymphoma resistant and susceptible chicken genotypes e) MDV oncoprotein Meq interacts with proteins involved in physiological processes central to lymphomagenesis.

Conclusions: In the context of the MD lymphoma microenvironment (and potentially in other CD30(hi) lymphomas as well), our results show that the neoplastic transformation is a continuum and the non-neoplastic cells are actually pre-neoplastic precursor cells and not merely immune bystanders. We also show that NF-κB is a central player in MDV induced neoplastic transformation of CD30-expressing lymphocytes in vivo. Our results provide insights into molecular mechanisms of neoplastic transformation in MD specifically and also herpesvirus induced lymphoma in general.

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Related in: MedlinePlus

Proteomics based network model showing differential expression of proteins in canonical cancer pathways and the intricate involvement of Meq, via hypothesized CD30-NF-κB-Meq pathway. Canonical Network model of proteome data using differential proteomic expression (CD30hi compared to CD30lo) mapped against cancer specific KEGG pathway “Pathways in cancer” and further modified by adding published Meq interaction and hypothesized Meq-CD30-NF-κB-Meq pathway. Light black solid lines indicate direct interaction, dotted lines indicate indirect interaction. Red dotted lines indicate our hypothesized CD30-NF-κB-Meq pathway. Literature based Meq interacting proteins are indicated by dark black lines originating from Meq.
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Figure 1: Proteomics based network model showing differential expression of proteins in canonical cancer pathways and the intricate involvement of Meq, via hypothesized CD30-NF-κB-Meq pathway. Canonical Network model of proteome data using differential proteomic expression (CD30hi compared to CD30lo) mapped against cancer specific KEGG pathway “Pathways in cancer” and further modified by adding published Meq interaction and hypothesized Meq-CD30-NF-κB-Meq pathway. Light black solid lines indicate direct interaction, dotted lines indicate indirect interaction. Red dotted lines indicate our hypothesized CD30-NF-κB-Meq pathway. Literature based Meq interacting proteins are indicated by dark black lines originating from Meq.

Mentions: To visualize the differences between the CD30hi and CD30lo lymphocytes proteomes (Figure1) in terms of well-studied cancer pathways, the differential protein expression data (Additional file1) was manually mapped to the cancer specific pathway “Pathways in cancer” from the Kyoto Encyclopedia of Genes and Genomes (KEGG)[25] (Figure1). This specific KEGG pathway is a map of several different interacting signaling pathways and so provides a comprehensive overview of the molecular signatures of CD30hi and CD30lo lymphocyte proteomes. We further modified the KEGG pathway by adding the Meq oncoprotein, previously published Meq interacting proteins, and our hypothesized Meq-CD30-NF-κB feed forward loop.


Nuclear Factor kappa B is central to Marek's disease herpesvirus induced neoplastic transformation of CD30 expressing lymphocytes in-vivo.

Kumar S, Kunec D, Buza JJ, Chiang HI, Zhou H, Subramaniam S, Pendarvis K, Cheng HH, Burgess SC - BMC Syst Biol (2012)

Proteomics based network model showing differential expression of proteins in canonical cancer pathways and the intricate involvement of Meq, via hypothesized CD30-NF-κB-Meq pathway. Canonical Network model of proteome data using differential proteomic expression (CD30hi compared to CD30lo) mapped against cancer specific KEGG pathway “Pathways in cancer” and further modified by adding published Meq interaction and hypothesized Meq-CD30-NF-κB-Meq pathway. Light black solid lines indicate direct interaction, dotted lines indicate indirect interaction. Red dotted lines indicate our hypothesized CD30-NF-κB-Meq pathway. Literature based Meq interacting proteins are indicated by dark black lines originating from Meq.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472249&req=5

Figure 1: Proteomics based network model showing differential expression of proteins in canonical cancer pathways and the intricate involvement of Meq, via hypothesized CD30-NF-κB-Meq pathway. Canonical Network model of proteome data using differential proteomic expression (CD30hi compared to CD30lo) mapped against cancer specific KEGG pathway “Pathways in cancer” and further modified by adding published Meq interaction and hypothesized Meq-CD30-NF-κB-Meq pathway. Light black solid lines indicate direct interaction, dotted lines indicate indirect interaction. Red dotted lines indicate our hypothesized CD30-NF-κB-Meq pathway. Literature based Meq interacting proteins are indicated by dark black lines originating from Meq.
Mentions: To visualize the differences between the CD30hi and CD30lo lymphocytes proteomes (Figure1) in terms of well-studied cancer pathways, the differential protein expression data (Additional file1) was manually mapped to the cancer specific pathway “Pathways in cancer” from the Kyoto Encyclopedia of Genes and Genomes (KEGG)[25] (Figure1). This specific KEGG pathway is a map of several different interacting signaling pathways and so provides a comprehensive overview of the molecular signatures of CD30hi and CD30lo lymphocyte proteomes. We further modified the KEGG pathway by adding the Meq oncoprotein, previously published Meq interacting proteins, and our hypothesized Meq-CD30-NF-κB feed forward loop.

Bottom Line: The exact mechanism of neoplastic transformation from CD30(lo) expressing phenotype to CD30(hi) expressing neoplastic phenotype is unknown.Here, using microarray, proteomics and Systems Biology modeling; we compare the global gene expression of CD30(lo) and CD30(hi) cells to identify key pathways of neoplastic transformation.We propose and test a specific mechanism of neoplastic transformation, and genetic resistance, involving the MDV oncogene Meq, host gene products of the Nuclear Factor Kappa B (NF-κB) family and CD30; we also identify a novel Meq protein interactome.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathobiology and Population Medicine, Mississippi State University, MS 39762, USA. skumar@cvm.msstate.edu

ABSTRACT

Background: Marek's Disease (MD) is a hyperproliferative, lymphomatous, neoplastic disease of chickens caused by the oncogenic Gallid herpesvirus type 2 (GaHV-2; MDV). Like several human lymphomas the neoplastic MD lymphoma cells overexpress the CD30 antigen (CD30(hi)) and are in minority, while the non-neoplastic cells (CD30(lo)) form the majority of population. MD is a unique natural in-vivo model of human CD30(hi) lymphomas with both natural CD30(hi) lymphomagenesis and spontaneous regression. The exact mechanism of neoplastic transformation from CD30(lo) expressing phenotype to CD30(hi) expressing neoplastic phenotype is unknown. Here, using microarray, proteomics and Systems Biology modeling; we compare the global gene expression of CD30(lo) and CD30(hi) cells to identify key pathways of neoplastic transformation. We propose and test a specific mechanism of neoplastic transformation, and genetic resistance, involving the MDV oncogene Meq, host gene products of the Nuclear Factor Kappa B (NF-κB) family and CD30; we also identify a novel Meq protein interactome.

Results: Our results show that a) CD30(lo) lymphocytes are pre-neoplastic precursors and not merely reactive lymphocytes; b) multiple transformation mechanisms exist and are potentially controlled by Meq; c) Meq can drive a feed-forward cycle that induces CD30 transcription, increases CD30 signaling which activates NF-κB, and, in turn, increases Meq transcription; d) Meq transcriptional repression or activation of the CD30 promoter generally correlates with polymorphisms in the CD30 promoter distinguishing MD-lymphoma resistant and susceptible chicken genotypes e) MDV oncoprotein Meq interacts with proteins involved in physiological processes central to lymphomagenesis.

Conclusions: In the context of the MD lymphoma microenvironment (and potentially in other CD30(hi) lymphomas as well), our results show that the neoplastic transformation is a continuum and the non-neoplastic cells are actually pre-neoplastic precursor cells and not merely immune bystanders. We also show that NF-κB is a central player in MDV induced neoplastic transformation of CD30-expressing lymphocytes in vivo. Our results provide insights into molecular mechanisms of neoplastic transformation in MD specifically and also herpesvirus induced lymphoma in general.

Show MeSH
Related in: MedlinePlus