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Upregulation of the alternative splicing factor NOVA2 in colorectal cancer vasculature

Authors Gallo S, Arcidiacono MV, Tisato V, Piva R, Penolazzi L, Bosi C, Feo CV, Gafà R, Secchiero P

Received 20 April 2018

Accepted for publication 25 June 2018

Published 20 September 2018 Volume 2018:11 Pages 6049—6056

DOI https://doi.org/10.2147/OTT.S171678

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Cristina Weinberg

Peer reviewer comments 4

Editor who approved publication: Prof. Dr. Geoffrey Pietersz


Stefania Gallo,1,* Maria Vittoria Arcidiacono,2,* Veronica Tisato,1 Roberta Piva,3 Letizia Penolazzi,3 Cristina Bosi,1 Carlo V Feo,1 Roberta Gafà,1 Paola Secchiero1

1Department of Morphology, Surgery, Experimental Medicine and LTTA Center, University of Ferrara, Ferrara, Italy; 2Institute for Maternal and Child Health, IRCCS “Burlo Garofolo,” Trieste, Italy; 3Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy

*These authors contributed equally to this work

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 HIF1α, 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.

Keywords: NOVA2, tumor angiogenesis, colorectal cancer, hypoxia

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