Genes mapped at the genomic loci 11q13.4-q24.3 interval are
associated with cell adhesion and inflammation pathways
To investigate the association between CNAs in Ch11q and COX-2 protein
expression, we selected the cytobands with CNAs in the following genomic
loci of three patients in Group 2: 11q13.4-q25 (Pat15 and Pat20), and
11q12.1-q25 (Pat42), with a common interval among all three patients at
11q13.4-q24.3 (Figure 3A). Identification of the genes mapped in the
common interval revealed a total of 409 protein-coding genes and 34
miRNAs (Supplemental Tables S1, S2 and S3). Kyoto Encyclopedia of Genes
and Genomes (KEGG) pathway enrichment analysis (DIANA-miRPath v.3)
associated 14 of the miRNAs with glycosphingolipid, fatty acid, and
steroid hormone biosynthesis and cell adhesion molecules (Supplemental
Table S4). Using TarBase v.7.0 miRNA target prediction analysis, 39
targets were predicted to be regulated by these miRNAs.
The list composed of the 409 protein-coding genes, the 39 miRNA targets,
and the 30 inflammation-related genes 17, 30 was used
to generate a PPI network. It resulted in a network with 469 nodes and
476 edges (Figure 4A), with a PPI enrichment p-value of 1.0e-16, which
indicates that proteins in the network present more mutual interactions
than expected. Surprisingly, no direct connection was found betweenPTGS2 and Ch11q-related genes. Thus, indirect relationship
analysis was performed by applying the degree, betweenness, and
eigenvector centrality. Ninety-two out of the 469 nodes were of more
topological relevance in the network: 29 hubs, 6 bottlenecks, 14
switches, and 30 HBS (Figure 4). Besides, gene ontologies (GO) analysis
revealed cell adhesion, transcription, DNA repair, and inflammation as
the main biological processes related to these genes. Clustering and GOs
analysis led to identifying five clusters (Figure 4B; Supplemental Table
S5). Cluster 1 is associated with the regulation of cytokine production,
immune system process, apoptosis, cell proliferation, programmed cell
death, and the mutual interaction of metalloproteinases (MMPs), which is
involved in the collagen metabolic process. Cell and biological adhesion
were the only processes associated with Clusters 2 and 4. ThePTGS2 gene is an HBS node found only in cluster 3, where its
interaction with other genes of the PGE2 and other inflammatory pathways
is evident, as well as its indirect interaction with CLPB(chromosome location Ch11q13.4), a gene involved in the cellular heat
response. In cluster 5, several genes were identified related to the
neurological system process, in addition to a connection of interleukin
6 (IL-6 ), IL-6 receptor (IL-6R ), and signal transducer and
activator of transcription 3 (STAT3 ), involved in IL-6-mediated
signaling pathway. The CLPB gene, together with PTGES3 andPTGER1, are common HBS between Clusters 3 and 5. Likewise, other
HBS nodes, such as the ones involving IL-1β and CEBPB ,
intersect between Clusters 1 and 3, while EP300 and STAT3are common HBS to Clusters 1, 3, and 5. Altogether, this analysis led to
identifying nodes of biological relevance that interconnect clusters
with different profiles of gene interactions, progressing toward
understanding the correlation of COX-2 expression and aberrations in
Ch11q.