“…ENSRNOT00000003428 had higher expression in the obese rats, while ENSRNOT00000042862 had higher expression in the lean controls. Although the biological functions of the isoforms of Epb4.1l5 are not well studied, the consistent difference in isoform usage in obese and lean animals indicates the two isoforms may play different roles in EMT during DN progression 29 . Figure 3 Exon structures and expression levels of Epb4.1l5 and its two transcripts.…”
Obese ZSF1 rats exhibit spontaneous time-dependent diabetic nephropathy and are considered to be a highly relevant animal model of progressive human diabetic kidney disease. We previously identified gene expression changes between disease and control animals across six time points from 12 to 41 weeks. In this study, the same data were analysed at the isoform and exon levels to reveal additional disease mechanisms that may be governed by alternative splicing. Our analyses identified alternative splicing patterns in genes that may be implicated in disease pathogenesis (such as Shc1, Serpinc1, Epb4.1l5, and Il-33), which would have been overlooked in standard gene-level analysis. The alternatively spliced genes were enriched in pathways related to cell adhesion, cell–cell interactions/junctions, and cytoskeleton signalling, whereas the differentially expressed genes were enriched in pathways related to immune response, G protein-coupled receptor, and cAMP signalling. Our findings indicate that additional mechanistic insights can be gained from exon- and isoform-level data analyses over standard gene-level analysis. Considering alternative splicing is poorly conserved between rodents and humans, it is noted that this work is not translational, but the point holds true that additional insights can be gained from alternative splicing analysis of RNA-seq data.
“…ENSRNOT00000003428 had higher expression in the obese rats, while ENSRNOT00000042862 had higher expression in the lean controls. Although the biological functions of the isoforms of Epb4.1l5 are not well studied, the consistent difference in isoform usage in obese and lean animals indicates the two isoforms may play different roles in EMT during DN progression 29 . Figure 3 Exon structures and expression levels of Epb4.1l5 and its two transcripts.…”
Obese ZSF1 rats exhibit spontaneous time-dependent diabetic nephropathy and are considered to be a highly relevant animal model of progressive human diabetic kidney disease. We previously identified gene expression changes between disease and control animals across six time points from 12 to 41 weeks. In this study, the same data were analysed at the isoform and exon levels to reveal additional disease mechanisms that may be governed by alternative splicing. Our analyses identified alternative splicing patterns in genes that may be implicated in disease pathogenesis (such as Shc1, Serpinc1, Epb4.1l5, and Il-33), which would have been overlooked in standard gene-level analysis. The alternatively spliced genes were enriched in pathways related to cell adhesion, cell–cell interactions/junctions, and cytoskeleton signalling, whereas the differentially expressed genes were enriched in pathways related to immune response, G protein-coupled receptor, and cAMP signalling. Our findings indicate that additional mechanistic insights can be gained from exon- and isoform-level data analyses over standard gene-level analysis. Considering alternative splicing is poorly conserved between rodents and humans, it is noted that this work is not translational, but the point holds true that additional insights can be gained from alternative splicing analysis of RNA-seq data.
“…Poor outcomes have been correlated with overexpression of EPB41L5 among patients with breast cancer, squamous cell carcinoma of the tongue, and upper urinary tract urothelial carcinoma (35)(36)(37)(38)(39)(40). Given that these prior studies have characterized the reliable prognostic value of EPB41L5 in other cancer types, it is plausible that EPB41L5 may represent a new biomarker for LG-PNETs with high propensity of metastasis.…”
Section: Figure 2 the Weak Epb41l5 Immunostaining Of A Primary Lg-pnmentioning
Background/Aim: Low-grade pancreatic neuroendocrine tumors (LG-PNETs) behave unpredictably. The aim of the study was to identify biomarkers that predict PNET metastasis to improve treatment selection. Patients and Methods: Five patients with primary non-metastatic LG-PNETs, six with primary LG-PNETs with synchronous or metachronous metastases (M-PNETs), and six metastatic to liver LG-PNETs (ML-PNETs) from the group of six M-PNET patients were selected. RNA data were normalized using iterative rank-order normalization. Student's t-test identified differentially-expressed genes in LG-PNETs versus M-PNETs. A 2-fold difference in expression was considered to be significant. Results were validated with an independent dataset of LG-PNETs and metastatic LG-PNETs. Results: Overall, 195 genes had a >2-fold change (in either direction). A total of 29 genes were differentially overexpressed in M-PNETs. Erythrocyte membrane protein band 4.1-like 5 (EPB41L5) had a 2.07-fold change increase in M-PNETs and the smallest p-value. EPB41L5 was not statistically different between M-PNETs and ML-PNETs. EPB41L5 differential expression between primary and metastatic LG-PNETs was confirmed by immunohistochemistry. Conclusion: These results support further investigation into whether EPB41L5 is a biomarker of PNETs with high risk for metastases. Pancreatic neuroendocrine tumors/carcinomas (PNETs/ PECAs) represent about 1-2% of all pancreatic tumors. Recently, however, it has been shown that PNETs have higher prevalence and malignant potential and result in considerable morbidity and mortality (1-4). This may be the result of increased physician awareness, increased use of advancements in imaging modalities, and the protracted clinical course of the disease (1). The oncogenic drivers responsible for the PNET metastatic phenotype have yet to be uncovered. As a result, these tumors are difficult to manage clinically because of their tendency to behave unpredictably (2). Indeed, even when considering low-grade PNETs (LG-PNETs), the presence of metastasis significantly affects patient survival and renders the tumors resistant to currently available therapies (5). Thus, the identification of a biomarker capable of identifying LG-PNETs at higher risk of metastasis may guide the clinical management of these tumors (3, 4). Published reports have shown that molecular alterations in PNETs include genomic alterations (GAs) in DNA damage repair genes MUTYH, CHEK2, and BRCA2 and inactivation of tumor suppressor genes and gene rearrangements that occur in MTAP, ARID2, SMARCA4, MLL3, CDKN2A, and SETD2 (6-12). Molecular analyses of PNETs have uncovered alterations in the pathways responsible for chromatin remodeling, DNA damage repair, activation of mammalian target of rapamycin (mTOR) signaling, and telomere maintenance. Moreover, gene expression profiling (GEP) of PNETs identified a subgroup of these tumors that are associated with hypoxia-inducible factor signaling (12). PNETs have also been reported to exhibit epithelial mesenchymal transition (EMT) b...
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