Assessment of BPV-1 Mediated Matrix Metalloproteinase Genes Deregulation in the In Vivo and In Vitro Models Designed to Explore Molecular Nature of Equine Sarcoids

Podstawski, Przemysław; Ropka‐Molik, Katarzyna; Semik-Gurgul, Ewelina; Samiec, M.; Skrzyszowska, M.; Podstawski, Zenon; Szmatoła, Tomasz; Witkowski, M.; Pawlina-Tyszko, Klaudia

doi:10.3390/cells11081268

Cited by 5 publications

(5 citation statements)

References 20 publications

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“…In this context, it is interesting to mention that in bovine cutaneous fibropapillomas, we demonstrated by immunohistochemistry a weak to moderate cytoplasmic and perinuclear collagenase MMP-1 expression, comparing to normal skin samples where a moderate reaction was seen; these differences in expression normal vs. tumors were confirmed biochemically, suggesting a potential contribution by potentiating the collagenolysis process. However, a recent study on in vivo and in vitro models designed to explore molecular nature of equine sarcoids indicate that BPV-1 infection contributes to diminished MMP-1 expression level ( 33 ), results which are consistent with our study. On the other hand, in knockdown MMP-1 cervical cancer cell lines it has been demonstrated a reduced invasion ability compared to the control, suggesting that knockdown of MMP-1 is responsible of reduced proliferation, invasion and migration ( 34 ).…”

Section: Discussionsupporting

confidence: 93%

Expression of collagenases (matrix metalloproteinase-1, -8, -13) and tissue inhibitor of metalloproteinase-3 (TIMP-3) in naturally occurring bovine cutaneous fibropapillomas

Bocaneti

Altamura²,

Corteggio³

et al. 2023

Front. Vet. Sci.

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Bovine cutaneous fibropapillomas are among the most common skin tumors in cattle; their etiology is associated with infection by bovine papillomavirus (BPV) types−1/-2 which are considered oncogenic. Degradation of the extracellular matrix (ECM), especially collagenolysis, is a key event during a series of relevant physiological processes, including tissue remodeling and repair. Various types of proteins are implicated in the regulation of ECM degradation: among these, matrix metalloproteinases (MMPs), a group of zinc-dependent endoenzymes, and tissue inhibitors of matrix metalloproteinases (TIMPs) are known to play a major role. Previous studies reported that aberrant expression of collagenolytic MMPs (MMP-1/-8/-13) and unbalancing between MMPs and TIMPs represent a critical step in tumor growth and invasion; however, studies regarding this topic in bovine cutaneous fibropapillomas are lacking. The aim of this study was to investigate the expression of the collagenases MMP-1/-8/-13 and TIMP-3 in naturally occurring fibropapillomas harboring BPV-2 DNA and normal skin samples. Here, by immunohistochemistry and western blotting analysis, we demonstrated overexpression of MMP-8/-13 along with a down-regulation of MMP-1, associated with a decrease in TIMP-3 levels in tumor compared with normal skin samples. This is the first study describing MMP-1/-8/-13 and TIMP−3 expression in bovine cutaneous fibropapillomas and our results suggest that an impaired expression of collagenases along with an imbalance between MMPs/TIMPs may contribute to an increased collagenolytic activity, which in turn could be important in ECM changes and tumors development.

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Section: Discussionsupporting

confidence: 93%

Expression of collagenases (matrix metalloproteinase-1, -8, -13) and tissue inhibitor of metalloproteinase-3 (TIMP-3) in naturally occurring bovine cutaneous fibropapillomas

Bocaneti

Altamura²,

Corteggio³

et al. 2023

Front. Vet. Sci.

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“…MMP-14 or MT1-MMP was originally identified as the extracellular protease responsible for activation of pro-MMP-2 ( 19 ). Interestingly, in BPV positive equine sarcoid an up-regulation of MMP-14 was demonstrated in several studies, which can explain the sarcoids' very or negligibly low capability to metastasize ( 15 , 20 ). Moreover, in human counterpart, Akgül and co-workers (2006) showed that expression of the HPV- 8 caused overexpression of MMP-14, suggesting a role of this MMP in the development of HPV-8 induced cutaneous tumors ( 9 ).…”

Section: Introductionmentioning

confidence: 97%

Expression of matrix metalloproteinases (MMPs)−2/-7/-9/-14 and tissue inhibitors of MMPs (TIMPs)−1/-2 in bovine cutaneous fibropapillomas associated with BPV-2 infection

et al. 2022

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IntroductionBovine papillomaviruses −1/−2 (BPVs) are small non-enveloped double-stranded DNA viruses able to infect the skin of bovids and equids, causing development of neoplastic lesions such as bovine cutaneous fibropapillomas and equine sarcoid. Matrix metalloproteinases (MMPs) are a group of zinc-dependent endopeptidases that degrade basal membrane and extracellular matrix, whose function is essential in physiological processes such as tissue remodeling and wound healing. MMPs activity is finely regulated by a balancing with expression of tissue inhibitors of MMPs (TIMPs), a process that is impaired during tumour development. BPV infection is associated with upregulation of MMPs and /or their unbalancing with TIMPs, contributing to local invasion and impairment of extracellular matrix remodeling in equine sarcoid; however, studies regarding this topic in bovine fibropapillomas are lacking.MethodsThe aim of this study was to perform an immunohistochemical and biochemical analysis on a panel of MMPs and TIMPs in BPV-2 positive bovine cutaneous fibropapillomas vs. normal skin samples.ResultsImmunohistochemistry revealed a cytoplasmic expression of MMP-2 (15/19), a cytoplasmic and perinuclear immunoreactivity of MMP-7 (19/19) and MMP-9 (19/19), along with a cytoplasmic and nuclear pattern of MMP-14 (16/19), accompanied by a cytoplasmic expression of TIMP-1 (14/19) and TIMP-2 (18/19) in tumour samples; western blotting revealed an overexpression of MMP-2 (8/9), MMP-7 (9/9) and MMP-9 (9/9), and a decreased level of MMP-14 (9/9), TIMP-1 (9/9) and TIMP-2 (9/9) in tumour versus normal skin samples. Moreover, gelatine zymography confirmed the expression of pro-active MMP-2 (9/9) and MMP-9 (9/9) and, most importantly, indicated the presence and increased activity of their active forms (82 and 62 kDa, respectively) in tumour samples.DiscussionThis is the first study describing MMPs and TIMPs in bovine cutaneous fibropapillomas and our results suggest that their unbalanced expression in presence of BPV-2 may play a significant role in tumour development. A further analysis of supplementary MMPs and TIMPs could bring new important insights into the papillomavirus induced tumours.

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“…Such high differences can indicate that ECM remodeling occurs, as in both human cancers and equine sarcoids. Interestingly, the previous study performed on sarcoids confirmed the significant over-expression of both MMP2 and MMP9 genes in the tumor tissue and in cell lines transfected with BPV-1 gene construct [ 31 ]. These findings strengthen the hypothesis that one of the main mechanisms responsible for sarcoid formation can be the FN1 –matrix metalloproteinase axis.…”

Section: Discussionmentioning

confidence: 87%

“…To establish DEGs involved in ECM remodeling and cell adhesion pathways, two sets of data obtained from our previous investigations were used (GSE193906 and GSE83430) [ 31 , 50 ]. The raw data annotated as GSE193906 were generated via NGS sequencing of two groups encompassing ACFC lines transfected with the BPV1-E1^E4 gene construct and control (i.e., non-transfected) ACFC lines.…”

Section: Methodsmentioning

confidence: 99%

Tracking the Molecular Scenarios for Tumorigenic Remodeling of Extracellular Matrix Based on Gene Expression Profiling in Equine Skin Neoplasia Models

Podstawski

Ropka‐Molik

Semik-Gurgul

et al. 2022

IJMS

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An important component of tissues is the extracellular matrix (ECM), which not only forms a tissue scaffold, but also provides the environment for numerous biochemical reactions. Its composition is strictly regulated, and any irregularities can result in the development of many diseases, including cancer. Sarcoid is the most common skin cancer in equids. Its formation results from the presence of the genetic material of the bovine papillomavirus (BPV). In addition, it is assumed that sarcoid-dependent oncogenic transformation arises from a disturbed wound healing process, which may be due to the incorrect functioning of the ECM. Moreover, sarcoid is characterized by a failure to metastasize. Therefore, in this study we decided to investigate the differences in the expression profiles of genes related not only to ECM remodeling, but also to the cell adhesion pathway, in order to estimate the influence of disturbances within the ECM on the sarcoid formation process. Furthermore, we conducted comparative research not only between equine sarcoid tissue bioptates and healthy skin-derived explants, but also between dermal fibroblast cell lines transfected and non-transfected with a construct encoding the E4 protein of the BP virus, in order to determine its effect on ECM disorders. The obtained results strongly support the hypothesis that ECM-related genes are correlated with sarcoid formation. The deregulated expression of selected genes was shown in both equine sarcoid tissue bioptates and adult cutaneous fibroblast cell (ACFC) lines neoplastically transformed by nucleofection with gene constructs encoding BPV1-E1^E4 protein. The identified genes (CD99, ITGB1, JAM3 and CADM1) were up- or down-regulated, which pinpointed the phenotypic differences from the backgrounds noticed for adequate expression pro-files in other cancerous or noncancerous tumors as reported in the available literature data. Unravelling the molecular pathways of ECM remodeling and cell adhesion in the in vivo and ex vivo models of epidermal/dermal sarcoid-related cancerogenesis might provide powerful tools for further investigations of genetic and epigenetic biomarkers for both silencing and re-initiating the processes of sarcoid-dependent neoplasia. Recognizing those biomarkers might insightfully explain the relatively high capacity of sarcoid-descended cancerous cell derivatives to epigenomically reprogram their nonmalignant neoplastic status in domestic horse cloned embryos produced by somatic cell nuclear transfer (SCNT).

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Assessment of BPV-1 Mediated Matrix Metalloproteinase Genes Deregulation in the In Vivo and In Vitro Models Designed to Explore Molecular Nature of Equine Sarcoids

Cited by 5 publications

References 20 publications

Expression of collagenases (matrix metalloproteinase-1, -8, -13) and tissue inhibitor of metalloproteinase-3 (TIMP-3) in naturally occurring bovine cutaneous fibropapillomas

Expression of collagenases (matrix metalloproteinase-1, -8, -13) and tissue inhibitor of metalloproteinase-3 (TIMP-3) in naturally occurring bovine cutaneous fibropapillomas

Expression of matrix metalloproteinases (MMPs)−2/-7/-9/-14 and tissue inhibitors of MMPs (TIMPs)−1/-2 in bovine cutaneous fibropapillomas associated with BPV-2 infection

Tracking the Molecular Scenarios for Tumorigenic Remodeling of Extracellular Matrix Based on Gene Expression Profiling in Equine Skin Neoplasia Models

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