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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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mRNA and protein correlation and GO based modeling of 88 concordantly expressed host gene products. Overall correlation (R2 = 0.0007) of protein and mRNA fold changes in CD30hi, compared to CD30lo lymphocytes ((A); n = 4592). Overall correlation for gene products differentially expressed in the same direction at both mRNA and protein levels showing higher correlation (n = 88, R2 = 0.5581). The triangles indicate genes known to be involved in CD30hi lymphomas, and have mRNA: protein correlation close to 1 (R2 = 0.92). CST3 is also involved in in CD30hi lymphomas but has very low mRNA: protein correlation. (B). Gene Ontology (GO) Biological Processes (BP) associated with the concordantly-expressed gene products indicates involvement in cellular processes perturbed in neoplastic transformation (C). Concordant gene products were ranked based mRNA: protein correlation and then grouped into pentiles and distribution of GO BP by pentile were compared. Cell cycle and proliferation are disproportionately represented in pentile 1 (D-i). Pentile 1 genes have more putative Meq binding sites in their promoters than genes in the other pentiles (mean ± sem) (D-ii).
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Figure 3: mRNA and protein correlation and GO based modeling of 88 concordantly expressed host gene products. Overall correlation (R2 = 0.0007) of protein and mRNA fold changes in CD30hi, compared to CD30lo lymphocytes ((A); n = 4592). Overall correlation for gene products differentially expressed in the same direction at both mRNA and protein levels showing higher correlation (n = 88, R2 = 0.5581). The triangles indicate genes known to be involved in CD30hi lymphomas, and have mRNA: protein correlation close to 1 (R2 = 0.92). CST3 is also involved in in CD30hi lymphomas but has very low mRNA: protein correlation. (B). Gene Ontology (GO) Biological Processes (BP) associated with the concordantly-expressed gene products indicates involvement in cellular processes perturbed in neoplastic transformation (C). Concordant gene products were ranked based mRNA: protein correlation and then grouped into pentiles and distribution of GO BP by pentile were compared. Cell cycle and proliferation are disproportionately represented in pentile 1 (D-i). Pentile 1 genes have more putative Meq binding sites in their promoters than genes in the other pentiles (mean ± sem) (D-ii).

Mentions: To identify potential direct transcriptional proteome regulation, we used the 44 K Agilent chicken microarray[71,72] to quantify mRNA and micro (mi)RNA (Additional file2) isolated from the same CD30hi and CD30lo lymphocytes which were used for proteomics and compared transcriptional fold changes with protein fold changes (Figure3A; Additional file3). Overall there was poor fold change correlation between mRNA and protein for 4592 host gene products (R2 = 0.0007). Next, to identify the key regulatory proteins responsible for neoplastic transformation, all the gene products which were differentially expressed in the same direction at both mRNA and protein levels were selected for further analysis. There are 88 gene products whose mRNA and protein fold changes were both significant and directionally consistent with each other (i.e. concordant) and these have an overall positive correlation (Figure3B, R2= 0.5581). Of these, on cross referencing with the published literature, revealed that BRCA2, CD30, CD40L, CST3 and PENK are known to be involved in human CD30hi lymphomas[17,51,73-79] and, except for CD30, all had decreased expression in CD30hi cells. BRCA2 is involved in error-free DNA-damage repair and decreased BRCA2 expression results in erroneous joining of DNA breaks[73]; CD30 is over-expressed in all human HL and some NHL[74,80]; CD40L prevents caspase-dependent and -independent PCD in HL cell lines[75]; CST3 is secreted by neoplastically transformed cells[76], inhibits neovascularization[81] and, via its inhibitory effect on cathepsin B and S, inhibits tumor invasion and metastasis[82] and is a biomarker in humans for NHL relapse[77]. CST3’s mRNA and protein decrease in MD CD30hi lymphocytes is consistent with human and murine lymphomas[77-79] and decreased CST3, enhances angiogenesis, tumor burden, tumor cell proliferation and tumor invasion[83] and also leads to increased expression of pro-neoplastic growth factor like IGF1 and FGF1 in mice[84]. In cells over-expressing NF-κB, and in coordination with TP53, PENK induces PCD[51], and so its decreased expression favors neoplasia.


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)

mRNA and protein correlation and GO based modeling of 88 concordantly expressed host gene products. Overall correlation (R2 = 0.0007) of protein and mRNA fold changes in CD30hi, compared to CD30lo lymphocytes ((A); n = 4592). Overall correlation for gene products differentially expressed in the same direction at both mRNA and protein levels showing higher correlation (n = 88, R2 = 0.5581). The triangles indicate genes known to be involved in CD30hi lymphomas, and have mRNA: protein correlation close to 1 (R2 = 0.92). CST3 is also involved in in CD30hi lymphomas but has very low mRNA: protein correlation. (B). Gene Ontology (GO) Biological Processes (BP) associated with the concordantly-expressed gene products indicates involvement in cellular processes perturbed in neoplastic transformation (C). Concordant gene products were ranked based mRNA: protein correlation and then grouped into pentiles and distribution of GO BP by pentile were compared. Cell cycle and proliferation are disproportionately represented in pentile 1 (D-i). Pentile 1 genes have more putative Meq binding sites in their promoters than genes in the other pentiles (mean ± sem) (D-ii).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: mRNA and protein correlation and GO based modeling of 88 concordantly expressed host gene products. Overall correlation (R2 = 0.0007) of protein and mRNA fold changes in CD30hi, compared to CD30lo lymphocytes ((A); n = 4592). Overall correlation for gene products differentially expressed in the same direction at both mRNA and protein levels showing higher correlation (n = 88, R2 = 0.5581). The triangles indicate genes known to be involved in CD30hi lymphomas, and have mRNA: protein correlation close to 1 (R2 = 0.92). CST3 is also involved in in CD30hi lymphomas but has very low mRNA: protein correlation. (B). Gene Ontology (GO) Biological Processes (BP) associated with the concordantly-expressed gene products indicates involvement in cellular processes perturbed in neoplastic transformation (C). Concordant gene products were ranked based mRNA: protein correlation and then grouped into pentiles and distribution of GO BP by pentile were compared. Cell cycle and proliferation are disproportionately represented in pentile 1 (D-i). Pentile 1 genes have more putative Meq binding sites in their promoters than genes in the other pentiles (mean ± sem) (D-ii).
Mentions: To identify potential direct transcriptional proteome regulation, we used the 44 K Agilent chicken microarray[71,72] to quantify mRNA and micro (mi)RNA (Additional file2) isolated from the same CD30hi and CD30lo lymphocytes which were used for proteomics and compared transcriptional fold changes with protein fold changes (Figure3A; Additional file3). Overall there was poor fold change correlation between mRNA and protein for 4592 host gene products (R2 = 0.0007). Next, to identify the key regulatory proteins responsible for neoplastic transformation, all the gene products which were differentially expressed in the same direction at both mRNA and protein levels were selected for further analysis. There are 88 gene products whose mRNA and protein fold changes were both significant and directionally consistent with each other (i.e. concordant) and these have an overall positive correlation (Figure3B, R2= 0.5581). Of these, on cross referencing with the published literature, revealed that BRCA2, CD30, CD40L, CST3 and PENK are known to be involved in human CD30hi lymphomas[17,51,73-79] and, except for CD30, all had decreased expression in CD30hi cells. BRCA2 is involved in error-free DNA-damage repair and decreased BRCA2 expression results in erroneous joining of DNA breaks[73]; CD30 is over-expressed in all human HL and some NHL[74,80]; CD40L prevents caspase-dependent and -independent PCD in HL cell lines[75]; CST3 is secreted by neoplastically transformed cells[76], inhibits neovascularization[81] and, via its inhibitory effect on cathepsin B and S, inhibits tumor invasion and metastasis[82] and is a biomarker in humans for NHL relapse[77]. CST3’s mRNA and protein decrease in MD CD30hi lymphocytes is consistent with human and murine lymphomas[77-79] and decreased CST3, enhances angiogenesis, tumor burden, tumor cell proliferation and tumor invasion[83] and also leads to increased expression of pro-neoplastic growth factor like IGF1 and FGF1 in mice[84]. In cells over-expressing NF-κB, and in coordination with TP53, PENK induces PCD[51], and so its decreased expression favors neoplasia.

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