Dataset Information

Upregulation of the alternative splicing factor NOVA2 in colorectal cancer vasculature.

ABSTRACT: Background:Tumor-specific isoforms generated by alternative splicing (AS) are demonstrated to contribute to tumor progression and can represent potential biomarkers. NOVA2 is an AS factor that in physiological conditions regulates endothelial cells' (ECs) polarity and vessel lumen maturation, likely by mediating AS of apical-basal polarity regulators. However, NOVA2 expression in tumor ECs and its regulation have never been investigated. Methods:To elucidate this, 40 colorectal cancer patients were enrolled and NOVA2 expression was investigated by immunohistochemistry in samples bearing both the normal mucosa and the tumor tissue. Results:NOVA2 was found expressed in ECs of tumor vasculature and, importantly, it was upregulated in tumor ECs with respect to normal mucosa ECs in all cases (P<0.001). The same samples analyzed by immunohistochemistry for the expression HIF1?, a marker of hypoxia, showed a positive and significant association with NOVA2 levels (P=0.045). Of note, NOVA2 was upregulated by hypoxia also in an in vitro ECs model. Conclusion:Our results provide, for the first time, evidence of NOVA2 expression and upregulation in tumor ECs and highlight hypoxia as a potential regulatory factor. These findings open a completely new perspective to study tumor vasculature and to uncover NOVA2 as a potential source of biomarkers and therapeutic targets based on AS isoforms.

SUBMITTER: Gallo S

PROVIDER: S-EPMC6157992 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Upregulation of the alternative splicing factor NOVA2 in colorectal cancer vasculature.

Gallo Stefania S Arcidiacono Maria Vittoria MV Tisato Veronica V Piva Roberta R Penolazzi Letizia L Bosi Cristina C Feo Carlo V CV Gafà Roberta R Secchiero Paola P

OncoTargets and therapy 20180920

<h4>Background</h4>Tumor-specific isoforms generated by alternative splicing (AS) are demonstrated to contribute to tumor progression and can represent potential biomarkers. NOVA2 is an AS factor that in physiological conditions regulates endothelial cells' (ECs) polarity and vessel lumen maturation, likely by mediating AS of apical-basal polarity regulators. However, NOVA2 expression in tumor ECs and its regulation have never been investigated.<h4>Methods</h4>To elucidate this, 40 colorectal ca ...[more]

PMID: 30275709

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Project description:BackgroundAlternative RNA splicing is widely dysregulated in cancers including lung adenocarcinoma, where aberrant splicing events are frequently caused by somatic splice site mutations or somatic mutations of splicing factor genes. However, the majority of mis-splicing in cancers is unexplained by these known mechanisms. We hypothesize that the aberrant Ras signaling characteristic of lung cancers plays a role in promoting the alternative splicing observed in tumors.MethodsWe recently performed transcriptome and proteome profiling of human lung epithelial cells ectopically expressing oncogenic KRAS and another cancer-associated Ras GTPase, RIT1. Unbiased analysis of phosphoproteome data identified altered splicing factor phosphorylation in KRAS-mutant cells, so we performed differential alternative splicing analysis using rMATS to identify significantly altered isoforms in lung epithelial cells. To determine whether these isoforms were uniquely regulated by KRAS, we performed a large-scale splicing screen in which we generated over 300 unique RNA sequencing profiles of isogenic A549 lung adenocarcinoma cells ectopically expressing 75 different wild-type or variant alleles across 28 genes implicated in lung cancer.ResultsMass spectrometry data showed widespread downregulation of splicing factor phosphorylation in lung epithelial cells expressing mutant KRAS compared to cells expressing wild-type KRAS. We observed alternative splicing in the same cells, with 2196 and 2416 skipped exon events in KRASG12V and KRASQ61H cells, respectively, 997 of which were shared (p < 0.001 by hypergeometric test). In the high-throughput splicing screen, mutant KRAS induced the greatest number of differential alternative splicing events, second only to the RNA binding protein RBM45 and its variant RBM45M126I. We identified ten high confidence cassette exon events across multiple KRAS variants and cell lines. These included differential splicing of the Myc Associated Zinc Finger (MAZ). As MAZ regulates expression of KRAS, this splice variant may be a mechanism for the cell to modulate wild-type KRAS levels in the presence of oncogenic KRAS.ConclusionProteomic and transcriptomic profiling of lung epithelial cells uncovered splicing factor phosphorylation and mRNA splicing events regulated by oncogenic KRAS. These data suggest that in addition to widespread transcriptional changes, the Ras signaling pathway can promote post-transcriptional splicing changes that may contribute to oncogenic processes.

Dataset Information

Upregulation of the alternative splicing factor NOVA2 in colorectal cancer vasculature.

Publications

Upregulation of the alternative splicing factor NOVA2 in colorectal cancer vasculature.

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