Abstract
BackgroundBovine papillomaviruses (BPVs) types 1 and 2 are the only known papillomaviruses able to jump the species. In fact, BPVs 1/2 induce neoplasia in their natural bovine host but infection is also associated to neoplastic skin lesions in equids termed sarcoids. The equine sarcoid is considered to be the most common equine cutaneous tumour worldwide for which no effective therapy is available. Very little is known about the molecular mechanisms underlying tumourigenesis, although genes contributing to sarcoid development have been identified. Several studies associate the development of cancer to the loss of function of a number of oncosuppressor genes. In this study the putative role of O6-methylguanine-DNA methyltrasferase (MGMT) was investigated for sarcoids. The expression of the oncosuppressor protein was assessed in normal and sarcoid cells and tissues. In addition, the DNA methylation profile was analysed to assess the role of epigenetic mechanism in regulation of MGMT expression.ResultsA group of 15 equine sarcoids and two primary sarcoid cell lines (fibroblasts) were analyzed for the expression of MGMT protein by immunohistochemistry, immunofluorescence and Western blotting techniques. The sarcoid cell line EqSO4b and the tumour samples showed a reduction or absence of MGMT expression. To investigate the causes of deregulated MGMT expression, ten samples were analyzed for the DNA methylation profile of the CpG island associated to the MGMT promoter. The analysis of 73 CpGs encompassing the region of interest showed in 1 out of 10 (10%) sarcoids a pronouncedly altered methylation profile when compared to the control epidermal sample. Similarily the EqSO4b cell line showed an altered MGMT methylation pattern in comparison to normal fibroblasts.ConclusionAs previously demonstrated for the oncosuppressor gene FHIT, analysis of MGMT expression in sarcoid tissues and a sarcoid-derived fibroblast cell line further suggests that oncosuppressor silencing may be also involved in BPV-induced equine tumours. Abnormal DNA methylation seems to be one of the possible molecular mechanisms involved in the alteration of MGMT expression. Further studies are required to address other basic molecular mechanisms involved in reduced MGMT expression. This study underlines the possible role of DNA methylation in oncosuppressor inactivation in equine sarcoids.
Highlights
Bovine papillomaviruses (BPVs) types 1 and 2 are the only known papillomaviruses able to jump the species
In order to gain new insights into possible mechanisms underlying BPV-mediated carcinogenesis, we investigated the status of methylguanine-DNA methyltrasferase (MGMT) protein expression in equine sarcoid cell lines and sarcoid tumours
In an ongoing study aiming at investigating the possible epigenetic changes of oncosuppressor genes involved in sarcoid carcinogenesis, we have recently demonstrated a noticeable alteration of expression of the FHIT protein (Strazzullo et al, 2012), which encouraged the investigation of the role of other oncosuppressor genes and of their regulative mechanisms in sarcoid molecular pathology
Summary
Bovine papillomaviruses (BPVs) types 1 and 2 are the only known papillomaviruses able to jump the species. The equine sarcoid is considered to be the most common equine cutaneous tumour worldwide for which no effective therapy is available. Very little is known about the molecular mechanisms underlying tumourigenesis, genes contributing to sarcoid development have been identified. Sarcoids vary and six different clinical types are recognized: occult, verrucous, nodular, fibroblastic, mixed and malevolent [2]. They are histologically characterized by disorganized dermal proliferation of spindle-shaped fibroblasts that form whorls and by epidermal hyperplasia, hyperkeratosis, and rete peg formation [3]. Little is known regarding the molecular mechanisms underlying sarcoid tumourigenesis and only few genes contributing to the development of this neoplastic disease have been identified so far [8]
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