OncoTargets and Therapy (Sep 2018)

Upregulation of the alternative splicing factor NOVA2 in colorectal cancer vasculature

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

Journal volume & issue
Vol. Volume 11
pp. 6049 – 6056

Abstract

Read online

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

Keywords