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Molecular Expression Profile Reveals Potential Biomarkers and Therapeutic Targets in Canine Endometrial Lesions.

Voorwald FA, Marchi FA, Villacis RA, Alves CE, Toniollo GH, Amorim RL, Drigo SA, Rogatto SR - PLoS ONE (2015)

Bottom Line: Global gene expression was detected using the Affymetrix Canine Gene 1.0 ST Array.In addition to S100A8 and S100A9 genes, overexpression of the inflammatory cytokines IL1B, TNF and IL6 as well as LTF were detected in the pyometra from treated animals.This molecular signature associated with potential biomarkers and therapeutic targets, such as CXCL10 and COX2, should guide future clinical studies.

View Article: PubMed Central - PubMed

Affiliation: Veterinary Clinic and Department of Surgery, São Paulo State University (UNESP), Jaboticabal, São Paulo, Brazil.

ABSTRACT
Cystic endometrial hyperplasia (CEH), mucometra, and pyometra are common uterine diseases in intact dogs, with pyometra being a life threatening disease. This study aimed to determine the gene expression profile of these lesions and potential biomarkers for closed-cervix pyometra, the most severe condition. Total RNA was extracted from 69 fresh endometrium samples collected from 21 healthy female dogs during diestrus, 16 CEH, 15 mucometra and 17 pyometra (eight open and nine closed-cervixes). Global gene expression was detected using the Affymetrix Canine Gene 1.0 ST Array. Unsupervised analysis revealed two clusters, one mainly composed of diestrus and CEH samples and the other by 12/15 mucometra and all pyometra samples. When comparing pyometra with other groups, 189 differentially expressed genes were detected. SLPI, PTGS2/COX2, MMP1, S100A8, S100A9 and IL8 were among the top up-regulated genes detected in pyometra, further confirmed by external expression data. Notably, a particular molecular profile in pyometra from animals previously treated with exogenous progesterone compounds was observed in comparison with pyometra from untreated dogs as well as with other groups irrespective of exogenous hormone treatment status. In addition to S100A8 and S100A9 genes, overexpression of the inflammatory cytokines IL1B, TNF and IL6 as well as LTF were detected in the pyometra from treated animals. Interestingly, closed pyometra was more frequently detected in treated dogs (64% versus 33%), with IL1B, TNF, LBP and CXCL10 among the most relevant overexpressed genes. This molecular signature associated with potential biomarkers and therapeutic targets, such as CXCL10 and COX2, should guide future clinical studies. Based on the gene expression profile we suggested that pyometra from progesterone treated dogs is a distinct molecular entity.

No MeSH data available.


Related in: MedlinePlus

Protein-protein interaction (PPI) networks in closed and open pyometra.PPI networks based on altered genes exclusively detected in closed pyometra and open pyometra and their interactive partners built and visualized with Navigator v.2.3. Potential candidates for biomarkers (B blue circles) and targets for therapy (Drugs, D orange circles) in closed pyometra and open pyometra are highlighted. Triangles represent the genes with altered expression in each group and are color-coded according to Gene Ontology (GO). Upright and inverted triangles indicate overexpressed and underexpressed genes, respectively.
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pone.0133894.g004: Protein-protein interaction (PPI) networks in closed and open pyometra.PPI networks based on altered genes exclusively detected in closed pyometra and open pyometra and their interactive partners built and visualized with Navigator v.2.3. Potential candidates for biomarkers (B blue circles) and targets for therapy (Drugs, D orange circles) in closed pyometra and open pyometra are highlighted. Triangles represent the genes with altered expression in each group and are color-coded according to Gene Ontology (GO). Upright and inverted triangles indicate overexpressed and underexpressed genes, respectively.

Mentions: In order to identify a molecular signature for closed pyometra, a life-threatening condition, the expression profile of closed pyometra compared with open pyometra was investigated (Fig 3C). Eighty-two differentially expressed genes were detected, but no significant difference was observed after Bonferroni correction. Characterization of exclusive molecular alterations in closed and open pyometra was also sought, with the aim of identifying putative biomarkers. Firstly, two lists of significant genes exclusively expressed in open pyometra versus diestrus and closed pyometra versus diestrus were generated and further compared to reveal exclusively altered genes in each group. Interestingly, closed pyometra revealed 70 exclusively altered genes, while open pyometra had 34 (S3 and S4 Tables, respectively). The top five-upregulated genes in closed pyometra were LBP, CCL3, IL1B, CXCL10 and ITGAM; while in open pyometra were FABP3, IL7, TNC, SDC1 and CLDN2. With the aim of revealing potential biomarkers and therapeutic targets for closed pyometra, a gene set enrichment analysis by IPA was performed, revealing 21 genes exclusively expressed in closed pyometra (Table 4). The IL1B gene, which encodes a proinflammatory cytokine, was detected as the highest upregulated gene (Fold change = 9.29, Table 4). Overexpression of the CXCL10, NNMT, MMP8, F3 and TNF genes was also identified in closed pyometra (Table 4). Thereafter, PPI networks were constructed using NAViGaTOR based on genes with altered expression detected exclusively in closed and open pyometra, in order to highlight potential biomarkers and/or therapeutic targets to therapy for each condition (Fig 4). In closed pyometra, four up-regulated genes were revealed as potential biomarkers and therapeutic targets, including CXCL10, IL1B, KDR, and TNF. The LBP gene, detected with the highest fold change, was indicated as a potential diagnostic marker in closed pyometra. In open pyometra, four overexpressed genes (ITGAV, FGFR3, SRC and PTGS1) were indicated as potential biomarkers and drug targets.


Molecular Expression Profile Reveals Potential Biomarkers and Therapeutic Targets in Canine Endometrial Lesions.

Voorwald FA, Marchi FA, Villacis RA, Alves CE, Toniollo GH, Amorim RL, Drigo SA, Rogatto SR - PLoS ONE (2015)

Protein-protein interaction (PPI) networks in closed and open pyometra.PPI networks based on altered genes exclusively detected in closed pyometra and open pyometra and their interactive partners built and visualized with Navigator v.2.3. Potential candidates for biomarkers (B blue circles) and targets for therapy (Drugs, D orange circles) in closed pyometra and open pyometra are highlighted. Triangles represent the genes with altered expression in each group and are color-coded according to Gene Ontology (GO). Upright and inverted triangles indicate overexpressed and underexpressed genes, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519320&req=5

pone.0133894.g004: Protein-protein interaction (PPI) networks in closed and open pyometra.PPI networks based on altered genes exclusively detected in closed pyometra and open pyometra and their interactive partners built and visualized with Navigator v.2.3. Potential candidates for biomarkers (B blue circles) and targets for therapy (Drugs, D orange circles) in closed pyometra and open pyometra are highlighted. Triangles represent the genes with altered expression in each group and are color-coded according to Gene Ontology (GO). Upright and inverted triangles indicate overexpressed and underexpressed genes, respectively.
Mentions: In order to identify a molecular signature for closed pyometra, a life-threatening condition, the expression profile of closed pyometra compared with open pyometra was investigated (Fig 3C). Eighty-two differentially expressed genes were detected, but no significant difference was observed after Bonferroni correction. Characterization of exclusive molecular alterations in closed and open pyometra was also sought, with the aim of identifying putative biomarkers. Firstly, two lists of significant genes exclusively expressed in open pyometra versus diestrus and closed pyometra versus diestrus were generated and further compared to reveal exclusively altered genes in each group. Interestingly, closed pyometra revealed 70 exclusively altered genes, while open pyometra had 34 (S3 and S4 Tables, respectively). The top five-upregulated genes in closed pyometra were LBP, CCL3, IL1B, CXCL10 and ITGAM; while in open pyometra were FABP3, IL7, TNC, SDC1 and CLDN2. With the aim of revealing potential biomarkers and therapeutic targets for closed pyometra, a gene set enrichment analysis by IPA was performed, revealing 21 genes exclusively expressed in closed pyometra (Table 4). The IL1B gene, which encodes a proinflammatory cytokine, was detected as the highest upregulated gene (Fold change = 9.29, Table 4). Overexpression of the CXCL10, NNMT, MMP8, F3 and TNF genes was also identified in closed pyometra (Table 4). Thereafter, PPI networks were constructed using NAViGaTOR based on genes with altered expression detected exclusively in closed and open pyometra, in order to highlight potential biomarkers and/or therapeutic targets to therapy for each condition (Fig 4). In closed pyometra, four up-regulated genes were revealed as potential biomarkers and therapeutic targets, including CXCL10, IL1B, KDR, and TNF. The LBP gene, detected with the highest fold change, was indicated as a potential diagnostic marker in closed pyometra. In open pyometra, four overexpressed genes (ITGAV, FGFR3, SRC and PTGS1) were indicated as potential biomarkers and drug targets.

Bottom Line: Global gene expression was detected using the Affymetrix Canine Gene 1.0 ST Array.In addition to S100A8 and S100A9 genes, overexpression of the inflammatory cytokines IL1B, TNF and IL6 as well as LTF were detected in the pyometra from treated animals.This molecular signature associated with potential biomarkers and therapeutic targets, such as CXCL10 and COX2, should guide future clinical studies.

View Article: PubMed Central - PubMed

Affiliation: Veterinary Clinic and Department of Surgery, São Paulo State University (UNESP), Jaboticabal, São Paulo, Brazil.

ABSTRACT
Cystic endometrial hyperplasia (CEH), mucometra, and pyometra are common uterine diseases in intact dogs, with pyometra being a life threatening disease. This study aimed to determine the gene expression profile of these lesions and potential biomarkers for closed-cervix pyometra, the most severe condition. Total RNA was extracted from 69 fresh endometrium samples collected from 21 healthy female dogs during diestrus, 16 CEH, 15 mucometra and 17 pyometra (eight open and nine closed-cervixes). Global gene expression was detected using the Affymetrix Canine Gene 1.0 ST Array. Unsupervised analysis revealed two clusters, one mainly composed of diestrus and CEH samples and the other by 12/15 mucometra and all pyometra samples. When comparing pyometra with other groups, 189 differentially expressed genes were detected. SLPI, PTGS2/COX2, MMP1, S100A8, S100A9 and IL8 were among the top up-regulated genes detected in pyometra, further confirmed by external expression data. Notably, a particular molecular profile in pyometra from animals previously treated with exogenous progesterone compounds was observed in comparison with pyometra from untreated dogs as well as with other groups irrespective of exogenous hormone treatment status. In addition to S100A8 and S100A9 genes, overexpression of the inflammatory cytokines IL1B, TNF and IL6 as well as LTF were detected in the pyometra from treated animals. Interestingly, closed pyometra was more frequently detected in treated dogs (64% versus 33%), with IL1B, TNF, LBP and CXCL10 among the most relevant overexpressed genes. This molecular signature associated with potential biomarkers and therapeutic targets, such as CXCL10 and COX2, should guide future clinical studies. Based on the gene expression profile we suggested that pyometra from progesterone treated dogs is a distinct molecular entity.

No MeSH data available.


Related in: MedlinePlus