Type

Journal Article

Authors

Gregor S Kijanka
Elaine W Kay
Richard O'Kennedy
Robert Cummins
Anthony O'Grady
Katherine M Sheehan
Lance Liotta
Virginia Espina
Seán Fitzgerald

Subjects

Biochemistry

Topics
colorectal cancer stromal cells tumor microenvironment epithelial cells tumor cells protein expression transcription factors gene expression

Stromal TRIM28-associated signaling pathway modulation within the colorectal cancer microenvironment. (2017)

Abstract Stromal gene expression patterns predict patient outcomes in colorectal cancer. TRIM28 is a transcriptional co-repressor that regulates an abundance of genes through the KRAB domain family of transcription factors. We have previously shown that stromal expression of TRIM28 is a marker of disease relapse and poor survival in colorectal cancer. Here, we perform differential epithelium-stroma proteomic network analyses to characterize signaling pathways associated with TRIM28 within the tumor microenvironment. Reverse phase protein arrays were generated from laser capture micro-dissected carcinoma and stromal cells from fresh frozen colorectal cancer tissues. Phosphorylation and total protein levels were measured for 30 cancer-related signaling pathway endpoints. Strength and direction of associations between signaling endpoints were identified using Spearman's rank-order correlation analysis and compared to TRIM28 levels. Expression status of TRIM28 in tumor epithelium and stromal fibroblasts was assessed using IHC in formalin fixed tissue and the epithelium to stroma protein expression ratio method. We found distinct proteomic networks in the epithelial and stromal compartments which were linked to expression levels of TRIM28. Low levels of TRIM28 in tumor stroma (high epithelium: stroma ratio) were found in 10 out of 19 cases. Upon proteomic network analyses, these stromal high ratio cases revealed moderate signaling pathway similarity exemplified by 76 significant Spearman correlations (ρ ≥ 0.75, p ≤ 0.01). Furthermore, low levels of stromal TRIM28 correlated with elevated MDM2 levels in tumor epithelium (p = 0.01) and COX-2 levels in tumor stroma (p = 0.002). Low TRIM28 epithelium to stroma ratios were associated with elevated levels of caspases 3 and 7 in stroma (p = 0.041 and p = 0.036) and an increased signaling pathway similarity in stromal cells with 81 significant Spearman correlations (ρ ≥ 0.75, p ≤ 0.01). By dissecting TRIM28-associated pathways in stromal fibroblasts and epithelial tumor cells, we performed comprehensive proteomic analyses of molecular networks within the tumor microenvironment. We found modulation of several signaling pathways associated with TRIM28, which may be attributed to the pleiotropic properties of TRIM28 through its translational suppression of the family of KRAB domain transcription factors in tumor stromal compartments.
Collections Ireland -> Dublin City University -> PubMed

Full list of authors on original publication

Gregor S Kijanka, Elaine W Kay, Richard O'Kennedy, Robert Cummins, Anthony O'Grady, Katherine M Sheehan, Lance Liotta, Virginia Espina, Seán Fitzgerald

Experts in our system

1
Gregor Kijanka
Dublin City University
 
2
Elaine W Kay
Royal College of Surgeons in Ireland
Total Publications: 153
 
3
R O'Kennedy
Dublin City University
Total Publications: 197
 
4
Robert Cummins
Royal College of Surgeons in Ireland
Total Publications: 22
 
5
Anthony O'Grady
Royal College of Surgeons in Ireland
Total Publications: 35
 
6
K M Sheehan
Dublin City University
Total Publications: 13
 
7
Lance Liotta
Dublin City University
Total Publications: 4
 
8
Virginia Espina
Dublin City University
Total Publications: 4
 
9
Seán Fitzgerald
Dublin City University
Total Publications: 5