Abstract
LOXL2 (lysyl oxidase-like 2), an enzyme that catalyzes oxidative deamination of lysine residue, is upregulated in esophageal squamous cell carcinoma (ESCC). A LOXL2 splice variant LOXL2-e13 and its wild type were overexpressed in ESCC cells followed by microarray analyses. In this study, we explored the potential role and molecular mechanism of LOXL2-e13 based on known protein-protein interactions (PPIs), following microarray analysis of KYSE150 ESCC cells overexpressing a LOXL2 splice variant, denoted by LOXL2-e13, or its wild-type counterpart. The differentially expressed genes (DEGs) of LOXL2-WT and LOXL2-e13 were applied to generate individual PPI subnetworks in which hundreds of DEGs interacted with thousands of other proteins. These two DEG groups were annotated by Functional Annotation Chart analysis in the DAVID bioinformatics database and compared. These results found many specific annotations indicating the potential specific role or mechanism for LOXL2-e13. The DEGs of LOXL2-e13, comparing to its wild type, were prioritized by the Random Walk with Restart algorithm. Several tumor-related genes such as ERO1L, ITGA3, and MAPK8 were found closest to LOXL2-e13. These results provide helpful information for subsequent experimental identification of the specific biological roles and molecular mechanisms of LOXL2-e13. Our study also provides a work flow to identify potential roles of splice variants with large scale data.
Highlights
The lysyl oxidase (LOX) family, which is composed of five enzymes (LOX and LOXL1/2/3/4), catalyzes oxidative deamination of lysine residues in their protein substrates, generating highly reactive aldehyde residues that initiate inter- and intramolecular cross-linkages [1]
To find how many and what kinds of proteins are connected with the differentially expressed genes (DEGs), two protein-protein interactions (PPIs) subnetworks were constructed by mapping the LOXL2-WT-DEGs and LOXL2-e13-DEGs to the Human Protein Reference Database (HPRD)&Biological General Repository for Interaction Datasets (BioGRID) parent PPI network to generate their respective PPI subnetworks
The LOXL2-WT-DEGs PPI subnetwork was composed of 6429 nodes and 97233 edges with 821 DEGs (Figure 1(c))
Summary
The lysyl oxidase (LOX) family, which is composed of five enzymes (LOX and LOXL1/2/3/4), catalyzes oxidative deamination of lysine residues in their protein substrates, generating highly reactive aldehyde residues that initiate inter- and intramolecular cross-linkages [1]. LOXL2 has been emphasized in recent years because of its critical roles in carcinomas. Upregulation of LOXL2 has been detected in many tumor cell lines or clinical samples and closely correlates with tumor invasion and metastasis [8,9,10,11]. Secreted LOXL2 is able to mediate extracellular matrix remodeling by upregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1) and matrix metalloproteinase (MMP-9) [13]. Intracellular LOXL2 is able to positively regulate the epithelial-mesenchymal transition (EMT) inducer Snail by enhancing Snail stability and functional activity and promoting EMT and tumor progression through downregulation of E-cadherin [14]. LOXL2 modulates focal adhesions, tight junctions, and cell polarity complexes in basal breast carcinoma cells through activation of the
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