Enzootic nasal tumor virus type 2 envelope of goats acts as a retroviral oncogene in cell transformation
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ORIGINAL PAPER
Enzootic nasal tumor virus type 2 envelope of goats acts as a retroviral oncogene in cell transformation Naoyoshi Maeda1 · Yasuo Inoshima3 · Marcelo De las Heras4 · Katsumi Maenaka1,2 Received: 23 July 2020 / Accepted: 30 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Enzootic nasal tumor virus type 1 (ENTV-1) (ovine nasal tumor virus) and ENTV-2 (caprine nasal tumor virus) are known to be causative agents of enzootic nasal adenocarcinoma (ENA) in sheep and goats, respectively. Although the nucleotide and amino acid sequences of ENTV-1 and ENTV-2 are quite similar, they are recognized as phylogenetically distinct viruses. The envelope protein of ENTV-1 functions as an oncoprotein in the in vitro transformation of epithelial cells and fibroblasts. Thus, it is the primary determinant of in vivo tumorigenesis in ENA. As per our knowledge, no previous studies have reported in detail the role of ENTV-2 in ENA tumorigenesis. Here, in order to investigate the molecular mechanism of caprine ENA oncogenesis by ENTV-2, we have attempted to identify the transforming potential of ENTV-2 envelope, and investigated the activation of cell signaling pathways in oncogenic transformation. Our findings confirmed that ENTV-2 envelope was capable of inducing oncogenic transformation of rat cell lines in vitro. Further, we found that MAPK, Akt, and p38 were constitutively activated in ENTV-2 envelope-transformed clone cells. In addition, inhibitor experiments revealed that MEK-MAPK and PI3K-Akt signaling pathways are involved in the ENTV-2 envelope-induced cell transformation. These data indicate that ENTV-2 envelope could induce oncogenic transformation by signaling pathways that are also utilized by ENTV-1 envelope. Keywords Envelope · Enzootic nasal adenocarcinoma · Enzootic nasal tumor virus · Jaagsiekte sheep retrovirus · Oncogenic transformation · Signal transduction
Introduction Enzootic nasal adenocarcinoma (ENA), previously known as enzootic intranasal tumor, is a contagious neoplasia in sheep and goats [1]. It has been reported worldwide [2–9], with several cases being reported in China in recent times Edited by Takeshi Noda. * Naoyoshi Maeda [email protected] 1
Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita‑12, Nishi‑6, Kita‑ku, Sapporo 060‑0812, Japan
2
Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita‑12, Nishi‑6, Kita‑ku, Sapporo 060‑0812, Japan
3
Laboratory of Food and Environmental Hygiene, Cooperative Department of Veterinary Medicine, Gifu University, 1‑1 Yanagido, Gifu 501‑1193, Japan
4
Department of Animal Pathology, Zaragoza University, Zaragoza, Spain
[10–13]. The etiological agent of ENA has been identified as retroviruses [14–17]. Experimental infection was successful in inducing ENA by cell-free tumor filtrates in sheep [18–20], and by concentrated ENA nasal exudate in goats [21]. The sequences of ovine na
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