scholarly journals DETECTing Merkel cell Polyomavirus in Merkel Tumours

2019 ◽  
Author(s):  
Reety Arora ◽  
Komal Gupta ◽  
Anjali Vijaykumar ◽  
Sudhir Krishna
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Antigen Expression ◽  
T Antigen ◽  
Merkel Cell Polyomavirus ◽  
Molecular Diagnostic ◽  
Merkel Cell ◽  
Immunohistochemical Studies ◽  
Near Future

AbstractMerkel cell carcinoma (MCC) is a rare, aggressive skin cancer caused either by Merkel cell polyomavirus (MCV) T antigen expression, post integration (∼80% cases), or by UV mediated DNA damage. Interestingly, overall survival of patients suffering from MCV positive Merkel cell carcinoma is better, making this differential information of significant diagnostic and prognostic value. Also, MCV as a causative agent also provides a direct target for therapy in virus positive MCC patients. Currently, the methods used for diagnosis of MCV in tumours are often tedious, discordant and unreliable. In this study we used a guided molecular scissors based - DNA Endonuclease Targeted CRISPR Trans Reporter (DETECTR) technique to develop an in vitro molecular diagnostic tool for MCV positive MCC. DETECTR couples recombinase polymerase based amplification of target MCV DNA with Cas12a mediated detection. CRISPR diagnostics couple specific detection followed by cutting of the pathogenic DNA by the Cas enzyme – gRNA complex, with non-specific cutting of ssDNA that provides a measurable visual cue. To detect MCV DNA in MCC tumours, we designed Cas12a gRNAs targeting the MCV DNA and tested their targeting efficiency, and sensitivity using a fluorophore quencher labeled reporter assay. We show that this sophisticated MCV DETECTR system can detect MCV integrated in Merkel tumour rapidly, specifically and with femto-molar sensitivity. This new MCV DNA detecting system is promising and we hope it can be coupled with histopathological and immunohistochemical studies to diagnose the viral status of MCC in clinics in the near future.

scholarly journals Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 919 ◽  
Author(s):  
Bhavishya Sarma ◽  
Christoph Willmes ◽  
Laura Angerer ◽  
Christian Adam ◽  
Jürgen C. Becker ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Antigen Expression ◽  
T Antigen ◽  
Merkel Cell ◽  
T Antigens ◽  
Growth And Survival ◽  
Proliferative Effect

Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate—a drug used to treat malaria—has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and β-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy.

scholarly journals Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors

2009 ◽  
Vol 125 (6) ◽  
pp. 1243-1249 ◽  
Author(s):  
Masahiro Shuda ◽  
Reety Arora ◽  
Hyun Jin Kwun ◽  
Huichen Feng ◽  
Ronit Sarid ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Antigen Expression ◽  
T Antigen ◽  
Merkel Cell Polyomavirus ◽  
Lymphoid Tissues ◽  
Merkel Cell

Significant overexpression of the Merkel cell polyomavirus (MCPyV) large T antigen in Merkel cell carcinoma

Head & Neck ◽  
2012 ◽  
Vol 35 (2) ◽  
pp. 184-189 ◽  
Author(s):  
Boban M. Erovic ◽  
Ayman Al Habeeb ◽  
Luke Harris ◽  
David P. Goldstein ◽  
Danny Ghazarian ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
T Antigen ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
Large T Antigen

scholarly journals Merkel Cell Polyomavirus Small T Antigen Mediates Microtubule Destabilization To Promote Cell Motility and Migration

2014 ◽  
Vol 89 (1) ◽  
pp. 35-47 ◽  
Author(s):  
Laura M. Knight ◽  
Gabriele Stakaityte ◽  
Jennifer, J. Wood ◽  
Hussein Abdul-Sada ◽  
David A. Griffiths ◽  
...  
Keyword(s):  
Skin Cancer ◽  
Cell Motility ◽  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Tumor Antigen ◽  
Molecular Mechanisms ◽  
T Antigen ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
Potential Link

ABSTRACTMerkel cell carcinoma (MCC) is an aggressive skin cancer of neuroendocrine origin with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) causes the majority of MCC cases due to the expression of the MCPyV small and large tumor antigens (ST and LT, respectively). Although a number of molecular mechanisms have been attributed to MCPyV tumor antigen-mediated cellular transformation or replication, to date, no studies have investigated any potential link between MCPyV T antigen expression and the highly metastatic nature of MCC. Here we use a quantitative proteomic approach to show that MCPyV ST promotes differential expression of cellular proteins implicated in microtubule-associated cytoskeletal organization and dynamics. Intriguingly, we demonstrate that MCPyV ST expression promotes microtubule destabilization, leading to a motile and migratory phenotype. We further highlight the essential role of the microtubule-associated protein stathmin in MCPyV ST-mediated microtubule destabilization and cell motility and implicate the cellular phosphatase catalytic subunit protein phosphatase 4C (PP4C) in the regulation of this process. These findings suggest a possible molecular mechanism for the highly metastatic phenotype associated with MCC.IMPORTANCEMerkel cell polyomavirus (MCPyV) causes the majority of cases of Merkel cell carcinoma (MCC), an aggressive skin cancer with a high metastatic potential. However, the molecular mechanisms leading to virally induced cancer development have yet to be fully elucidated. In particular, no studies have investigated any potential link between the virus and the highly metastatic nature of MCC. We demonstrate that the MCPyV small tumor antigen (ST) promotes the destabilization of the host cell microtubule network, which leads to a more motile and migratory cell phenotype. We further show that MCPyV ST induces this process by regulating the phosphorylation status of the cellular microtubule-associated protein stathmin by its known association with the cellular phosphatase catalytic subunit PP4C. These findings highlight stathmin as a possible biomarker of MCC and as a target for novel antitumoral therapies.

scholarly journals Merkel Cell Polyomavirus Infection, Large T Antigen, Retinoblastoma Protein and Outcome in Merkel Cell Carcinoma

2011 ◽  
Vol 17 (14) ◽  
pp. 4806-4813 ◽  
Author(s):  
Harri Sihto ◽  
Heli Kukko ◽  
Virve Koljonen ◽  
Risto Sankila ◽  
Tom Böhling ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Merkel Cell Carcinoma ◽  
Retinoblastoma Protein ◽  
T Antigen ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
Large T Antigen
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