Mutagenic Potential ofBos taurusPapillomavirus Type 1 E6 Recombinant Protein: First Description

Abstract

Bovine papillomavirus (BPV) is considered a useful model to study HPV oncogenic process. BPV interacts with the host chromatin, resulting in DNA damage, which is attributed to E5, E6, and E7 viral oncoproteins activity. However, the oncogenic mechanisms of BPV E6 oncoprotein per se remain unknown. This study aimed to evaluate the mutagenic potential of Bos taurus papillomavirus type 1 (BPV-1) E6 recombinant oncoprotein by the cytokinesis-block micronucleus assay (CBMNA) and comet assay (CA). Peripheral blood samples of five calves were collected. Samples were subjected to molecular diagnosis, which did not reveal presence of BPV sequences. Samples were treated with 1 μg/mL of BPV-1 E6 oncoprotein and 50 μg/mL of cyclophosphamide (positive control). Negative controls were not submitted to any treatment. The samples were submitted to the CBMNA and CA. The results showed that BPV E6 oncoprotein induces clastogenesis per se, which is indicative of genomic instability. These results allowed better understanding the mechanism of cancer promotion associated with the BPV E6 oncoprotein and revealed that this oncoprotein can induce carcinogenesis per se. E6 recombinant oncoprotein has been suggested as a possible vaccine candidate. Results pointed out that BPV E6 recombinant oncoprotein modifications are required to use it as vaccine.

Genetics and metabolic deregulation following cancer initiation: A world to explore

“…Mutagenic studies have attributed the BPV clastogenic potential to combined action of viral oncoproteins (E5, E6 and E7), that induce cell hyperproliferation and replication fork collapse [26,27,74,141]. In this sense, our group demonstrated that BPV E6 oncoprotein is able to induce clastogenesis and neosis per se [31]. Neosis, a novel type of cell-division, characterized by asymmetric, intracellular cytokinesis, producing several small mononuclear cells (Raju cells), which give rise to transformed cell lines [142] is an additional evidence of hyperproliferative action E6 oncoprotein.…”

“…However, cancer cell hyperproliferation lead to glycolysis activation (Warburg effect) to reduce ROS generation that, in excess, could induce the cell death. Moreover, cell hyperproliferation promotes replication fork collapse [97][98][99], resulting in DSBs [31]. DNA breaks are mutation sources that contribute to cell type heterogeneity, verified in tumor microenvironment.…”

“…For this reason, mutagen identification has been explored [13][14][15][16], since to avoid the long term exposure to these mutagens can be considered a protective method against cancer. Currently, it is known that several drugs [16][17][18], organic [19][20][21][22] and inorganic chemical compounds [23,24] and biological agents, including viruses [12,[25][26][27][28][29][30][31][32][33] are able to induce DNA damage.…”

Polyploid Giant Cancer Cells, a Hallmark of Oncoviruses and a New Therapeutic Challenge

“…Indeed, Zhang et al reported endoreduplication as a potential mechanism of PGCC formation after cobalt chloride treatment ( 163 ). HPV16 E5 is capable of inducing endoreplication ( 34 ), a mechanism shared by E6 oncoprotein as evidenced by the presence of intracellular cytokinesis ( 164 ). Transduction with HPV-18 E7 pushed the cells to reenter another round of S phase resulting in two consecutive S phases without cytokinesis, hence ensuing multinucleated cells with enlarged nuclei ( 35 ).…”

Modelagem estrutural e análise<i> In silico </i>da proteína E6 do genêro <i>Deltapapillomavirus</i>.

“…Porém, somente em 2014, usando a proteína recombinante E6 de BPV1 purificada (MAZZUCHELLI-DE-SOUZA et al, 2013), foi demonstrado o seu potencial oncogênico per se em cultura de linfócitos (ARALDI et al, 2015).…”