The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Heikki Joensuu - One of the best experts on this subject based on the ideXlab platform.
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chronic lymphocytic leukaemia patients have a high risk of Merkel Cell Polyomavirus dna positive Merkel Cell carcinoma
British Journal of Cancer, 2009Co-Authors: Virve Koljonen, Heli Kukko, Risto Sankila, Tom Böhling, Erkki Tukiainen, Eero Pukkala, Harri Sihto, Heikki JoensuuAbstract:Chronic lymphocytic leukaemia patients have a high risk of Merkel-Cell Polyomavirus DNA-positive Merkel-Cell carcinoma
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chronic lymphocytic leukaemia patients have a high risk of Merkel Cell Polyomavirus dna positive Merkel Cell carcinoma
British Journal of Cancer, 2009Co-Authors: Virve Koljonen, Heli Kukko, Risto Sankila, Tom Böhling, Erkki Tukiainen, Eero Pukkala, Harri Sihto, Heikki JoensuuAbstract:Immunosuppression and Merkel-Cell Polyomavirus (MCPyV) infection may have a role in the pathogenesis of Merkel-Cell carcinoma (MCC), a rare neuroendocrine carcinoma of the skin. We studied incidence of chronic lymphocytic leukaemia (CLL) and MCC from the files of the Finnish Cancer Registry and the largest hospital of Finland, Helsinki University Central Hospital, from 1979 to 2006. Presence of MCPyV DNA in MCCs was investigated by quantitative PCR. We identified 4164 patients diagnosed with CLL and 172 diagnosed with MCC. Six patients diagnosed with both diseases were found; CLL was the first diagnosis in four cases and MCC in two. The standardised incidence ratio (SIR) for CLL after the diagnosis of MCC was highly elevated, 17.9 (95% confidence interval (CI), 2.2–64.6; P<0.001), and the SIR for MCC after the diagnosis of CLL was also elevated, 15.7 (3.2–46.0, P<0.01). Merkel-Cell Polyomavirus DNA was present in all five MCCs with tumour tissue available for analysis. We conclude that patients diagnosed with CLL have a substantially increased risk for MCC, and vice versa. Merkel-Cell Polyomavirus DNA is frequently present in MCCs that occur in CLL patients. Immunosuppression related with CLL and viral infection might explain the association between CLL and MCC.
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clinical factors associated with Merkel Cell Polyomavirus infection in Merkel Cell carcinoma
Journal of the National Cancer Institute, 2009Co-Authors: Harri Sihto, Heli Kukko, Risto Sankila, Tom Böhling, Virve Koljonen, Heikki JoensuuAbstract:BACKGROUND: Merkel Cell carcinoma is a rare malignancy of the skin. Integration of Merkel Cell Polyomavirus (MCPyV) DNA to the tumor genome is frequent in these cancers. The clinical consequences of MCPyV infection are unknown. METHODS: We analyzed formalin-fixed paraffin-embedded Merkel Cell carcinoma tissue samples from 114 of 207 patients diagnosed with Merkel Cell carcinoma in Finland from 1979 to 2004 for the presence of MCPyV DNA with the use of polymerase chain reaction (PCR), quantitative PCR, and DNA sequencing and examined associations between tumor MCPyV DNA status and histopathologic factors and survival. The median follow-up time after Merkel Cell carcinoma diagnosis for subjects who were alive was 9.9 years (range = 4.9-21.9 years). All P values are two-sided. RESULTS: MCPyV DNA was present in 91 carcinomas (79.8%). Compared with MCPyV DNA-negative cancers, MCPyV DNA-positive cancers were more often located in a limb (40.7% vs 8.7%, P = .015) and less frequent in patients who had regional nodal metastases at diagnosis (6.6% vs 21.7%, P = .043). Patients with MCPyV DNA-positive tumors had better overall survival than those with MCPyV DNA-negative tumors (5-year survival: 45.0% vs 13.0%, respectively; P < .001, two-sided log-rank test). CONCLUSIONS: MCPyV infection is associated with clinical outcomes in patients with Merkel Cell carcinoma. These findings lend support to the hypothesis that viral infection is frequently associated with the pathogenesis of Merkel Cell carcinoma.
Patrick S Moore - One of the best experts on this subject based on the ideXlab platform.
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protein mediated viral latency is a novel mechanism for Merkel Cell Polyomavirus persistence
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: H J Kwun, Yuan Chang, Patrick S MooreAbstract:Viral latency, in which a virus genome does not replicate independently of the host Cell genome and produces no infectious particles, is required for long-term virus persistence. There is no known latency mechanism for chronic small DNA virus infections. Merkel Cell Polyomavirus (MCV) causes an aggressive skin cancer after prolonged infection and requires an active large T (LT) phosphoprotein helicase to replicate. We show that evolutionarily conserved MCV LT phosphorylation sites are constitutively recognized by Cellular Fbw7, βTrCP, and Skp2 Skp-F-box-cullin (SCF) E3 ubiquitin ligases, which degrade and suppress steady-state LT protein levels. Knockdown of each of these E3 ligases enhances LT stability and promotes MCV genome replication. Mutations at two of these phosphoreceptor sites [serine (S)220 and S239] in the full viral genome increase LT levels and promote MCV virion production and transmission, which can be neutralized with anti-capsid antibody. Virus activation is not mediated by viral gene transactivation, given that these mutations do not increase late gene transcription in the absence of genome replication. Mechanistic target of rapamycin inhibition by either nutrient starvation or use of an active site inhibitor reduces Skp2 levels and stabilizes LT, leading to enhanced MCV replication and transmission. MCV can sense stresses in its intraCellular environment, such as nutrient loss, through SCF E3 ligase activities, and responds by initiating active viral transmission. Protein-mediated viral latency through Cellular SCF E3 ligase targeting of viral replication proteins is a unique form of latency that may promote chronic viral persistence for some small DNA and RNA viruses.
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Merkel Cell Polyomavirus t antigens promote Cell proliferation and inflammatory cytokine gene expression
Journal of General Virology, 2015Co-Authors: Kathleen F Richards, Anna Guastafierro, Masahiro Shuda, Tuna Toptan, Patrick S Moore, Yuan ChangAbstract:Merkel Cell Polyomavirus (MCV) is clonally integrated in over 80 % of Merkel Cell carcinomas and mediates tumour development through the expression of viral oncoproteins, the large T (LT) and small T antigens (sT). Viral integration is associated with signature mutations in the T-antigen locus that result in deletions of C-terminal replicative functions of the LT antigen. Despite these truncations, the LT LXCXE retinoblastoma (Rb) pocket protein family binding domain is retained, and the entire sT isoform is maintained intact. To investigate the ability of MCV oncoproteins to regulate host gene expression, we performed microarray analysis on Cells stably expressing tumour-derived LT, tumour-derived LT along with sT, and tumour-derived LT with a mutated Rb interaction domain. Gene expression alterations in the presence of tumour-derived LT could be classified into three main groups: genes that are involved in the Cell cycle (specifically the G1/S transition), genes involved in DNA replication and genes involved in Cellular movement. The LXCXE mutant LT largely reversed gene expression alterations detected with the WT tumour-derived LT, while co-expression of sT did not significantly affect these patterns of gene expression. LXCXE-dependent upregulation of cyclin E and CDK2 correlated with increased proliferation in tumour-derived LT-expressing Cells. Tumour-derived LT and tumour-derived LT plus sT increased expression of multiple cytokines and chemokines, which resulted in elevated levels of secreted IL-8. We concluded that, in human fibroblasts, the LXCXE motif of tumour-derived LT enhances Cellular proliferation and upregulates Cell cycle and immune signalling gene transcription.
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restricted protein phosphatase 2a targeting by Merkel Cell Polyomavirus small t antigen
Journal of Virology, 2015Co-Authors: H J Kwun, Masahiro Shuda, Yuan Chang, Carlos J Camacho, Armin M Gamper, Mamie Thant, Patrick S MooreAbstract:ABSTRACT Merkel Cell Polyomavirus (MCV) is a newly discovered human cancer virus encoding a small T (sT) oncoprotein. We performed MCV sT FLAG-affinity purification followed by mass spectroscopy (MS) analysis, which identified several protein phosphatases (PP), including PP2A A and C subunits and PP4C, as potential Cellular interacting proteins. PP2A targeting is critical for the transforming properties of nonhuman Polyomaviruses, such as simian virus 40 (SV40), but is not required for MCV sT-induced rodent Cell transformation. We compared similarities and differences in PP2A binding between MCV and SV40 sT. While SV40 sT coimmunopurified with subunits PP2A Aα and PP2A C, MCV sT coimmunopurified with PP2A Aα, PP2A Aβ, and PP2A C. Scanning alanine mutagenesis at 29 sites across the MCV sT protein revealed that PP2A-binding domains lie on the opposite molecular surface from a previously described large T stabilization domain (LSD) loop that binds E3 ligases, such as Fbw7. MCV sT-PP2A interactions can be functionally distinguished by mutagenesis from MCV sT LSD-dependent 4E-BP1 hyperphosphorylation and viral DNA replication enhancement. MCV sT has a restricted range for PP2A B subunit substitution, inhibiting only the assembly of B56α into the phosphatase holoenzyme. In contrast, SV40 sT inhibits the assembly of B55α, B56α and B56e into PP2A. We conclude that MCV sT is required for Merkel Cell carcinoma growth, but its in vitro transforming activity depends on LSD interactions rather than PP2A targeting. IMPORTANCE Merkel Cell Polyomavirus is a newly discovered human cancer virus that promotes cancer, in part, through expression of its small T (sT) oncoprotein. Animal Polyomavirus sT oncoproteins have been found to cause experimental tumors by blocking the activities of a group of phosphatases called protein phosphatase 2A (PP2A). Our structural analysis reveals that MCV sT also displaces the B subunit of PP2A to inhibit PP2A activity. MCV sT, however, only displaces a restricted subset of PP2A B subunits, which is insufficient to cause tumor Cell formation in vitro . MCV sT instead transforms tumor Cells through another region called the large T stabilization domain. The PP2A targeting and transforming activities lie on opposite faces of the MCV sT molecule and can be genetically separated from each other.
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large t and small t antigens of Merkel Cell Polyomavirus
Current Opinion in Virology, 2015Co-Authors: J A Wendzicki, Patrick S Moore, Yuan ChangAbstract:Merkel Cell Polyomavirus (MCV) is the etiological agent of Merkel Cell carcinoma (MCC), a rare and highly lethal human skin cancer. A natural component of skin flora, MCV becomes tumorigenic only after integration into the host DNA together with specific mutations to the viral genome. Research on MCV large T (LT) and small T (sT) antigens, the only viral products expressed in MCC, shows that these major oncoproteins not only possess biochemical functions found in common with other Polyomavirus T antigens, but also demonstrate new Cellular targets not described in previous Polyomavirus models. This review provides a map of the relevant functional motifs and domains in MCV T antigens that have been identified, highlighting their roles in tumorigenesis.
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Merkel Cell Polyomavirus positive Merkel Cell carcinoma requires viral small t antigen for Cell proliferation
Journal of Investigative Dermatology, 2014Co-Authors: Masahiro Shuda, Yuan Chang, Patrick S MooreAbstract:To the Editor Angermeyer et al. (2013) claim that “Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma Cells Do Not Require Expression of the Viral Small T Antigen” (Angermeyer et al., 2013). This controversial conclusion is based on their inability to detect Merkel Cell Polyomavirus (MCV) small T (sT) protein expression and to inhibit Cell growth by putative sT knockdown in MCV-MCC Cells. These findings contradict existing evidence showing MCV sT protein expression in MCV-MCC cancer tissues (Shuda et al., 2011) and Cell lines (see Figure. 2, Houben et al., 2010) (Guastafierro et al., 2013). To investigate this discrepancy, we tried replicating Angermeyer et al's results using the same antibodies to detect MCV sT (CM8E6 (Kwunet al., 2009), CM5E1 (Shuda et al., 2011) and 2T2 ((Wang et al., 2012), kindly provided by C. Buck) on a panel of MCV-MCC Cell lines (Figure 1). MCV sT and large T (LT) are alternatively-spliced viral oncoproteins sharing a common N-terminus but having different C-termini, thus CM8E6 and 2T2 detects all isoforms of T antigens, while CM5E1 detects only sT and CM2B4 detects only LT and related isoforms. Differences in protein expression levels between MCV LT and sT are likely dependent on either premRNA or post-transcriptional protein processing. For positive and negative controls, we used UISO Cells transiently transfected with the MCV T antigen locus ({"type":"entrez-nucleotide","attrs":{"text":"JN038578","term_id":"354683949","term_text":"JN038578"}}JN038578) or with corresponding empty vector. UISO, commonly described as being from MCC origin (Houben et al., 2007), is negative for MCV and miRNA ontology studies show it clusters with Cell lines of breast cancer origin (Renwick et al., 2013). In contrast to Angermeyer et al., the 19 kD MCV sT band is readily detected in all MCV-MCC Cell lines (open arrows) but not in UISO Cells. Figure 1 Detection of Merkel Cell Polyomavirus (MCV) small T (sT) antigen expression by multiple MCV T antigen antibodies. Figure 2 Merkel Cell Polyomavirus (MCV) small T (sT) antigen knockdown inhibits MCV-positive Merkel Cell carcinoma (MCC) Cell proliferation.
Yuan Chang - One of the best experts on this subject based on the ideXlab platform.
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protein mediated viral latency is a novel mechanism for Merkel Cell Polyomavirus persistence
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: H J Kwun, Yuan Chang, Patrick S MooreAbstract:Viral latency, in which a virus genome does not replicate independently of the host Cell genome and produces no infectious particles, is required for long-term virus persistence. There is no known latency mechanism for chronic small DNA virus infections. Merkel Cell Polyomavirus (MCV) causes an aggressive skin cancer after prolonged infection and requires an active large T (LT) phosphoprotein helicase to replicate. We show that evolutionarily conserved MCV LT phosphorylation sites are constitutively recognized by Cellular Fbw7, βTrCP, and Skp2 Skp-F-box-cullin (SCF) E3 ubiquitin ligases, which degrade and suppress steady-state LT protein levels. Knockdown of each of these E3 ligases enhances LT stability and promotes MCV genome replication. Mutations at two of these phosphoreceptor sites [serine (S)220 and S239] in the full viral genome increase LT levels and promote MCV virion production and transmission, which can be neutralized with anti-capsid antibody. Virus activation is not mediated by viral gene transactivation, given that these mutations do not increase late gene transcription in the absence of genome replication. Mechanistic target of rapamycin inhibition by either nutrient starvation or use of an active site inhibitor reduces Skp2 levels and stabilizes LT, leading to enhanced MCV replication and transmission. MCV can sense stresses in its intraCellular environment, such as nutrient loss, through SCF E3 ligase activities, and responds by initiating active viral transmission. Protein-mediated viral latency through Cellular SCF E3 ligase targeting of viral replication proteins is a unique form of latency that may promote chronic viral persistence for some small DNA and RNA viruses.
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Merkel Cell Polyomavirus t antigens promote Cell proliferation and inflammatory cytokine gene expression
Journal of General Virology, 2015Co-Authors: Kathleen F Richards, Anna Guastafierro, Masahiro Shuda, Tuna Toptan, Patrick S Moore, Yuan ChangAbstract:Merkel Cell Polyomavirus (MCV) is clonally integrated in over 80 % of Merkel Cell carcinomas and mediates tumour development through the expression of viral oncoproteins, the large T (LT) and small T antigens (sT). Viral integration is associated with signature mutations in the T-antigen locus that result in deletions of C-terminal replicative functions of the LT antigen. Despite these truncations, the LT LXCXE retinoblastoma (Rb) pocket protein family binding domain is retained, and the entire sT isoform is maintained intact. To investigate the ability of MCV oncoproteins to regulate host gene expression, we performed microarray analysis on Cells stably expressing tumour-derived LT, tumour-derived LT along with sT, and tumour-derived LT with a mutated Rb interaction domain. Gene expression alterations in the presence of tumour-derived LT could be classified into three main groups: genes that are involved in the Cell cycle (specifically the G1/S transition), genes involved in DNA replication and genes involved in Cellular movement. The LXCXE mutant LT largely reversed gene expression alterations detected with the WT tumour-derived LT, while co-expression of sT did not significantly affect these patterns of gene expression. LXCXE-dependent upregulation of cyclin E and CDK2 correlated with increased proliferation in tumour-derived LT-expressing Cells. Tumour-derived LT and tumour-derived LT plus sT increased expression of multiple cytokines and chemokines, which resulted in elevated levels of secreted IL-8. We concluded that, in human fibroblasts, the LXCXE motif of tumour-derived LT enhances Cellular proliferation and upregulates Cell cycle and immune signalling gene transcription.
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restricted protein phosphatase 2a targeting by Merkel Cell Polyomavirus small t antigen
Journal of Virology, 2015Co-Authors: H J Kwun, Masahiro Shuda, Yuan Chang, Carlos J Camacho, Armin M Gamper, Mamie Thant, Patrick S MooreAbstract:ABSTRACT Merkel Cell Polyomavirus (MCV) is a newly discovered human cancer virus encoding a small T (sT) oncoprotein. We performed MCV sT FLAG-affinity purification followed by mass spectroscopy (MS) analysis, which identified several protein phosphatases (PP), including PP2A A and C subunits and PP4C, as potential Cellular interacting proteins. PP2A targeting is critical for the transforming properties of nonhuman Polyomaviruses, such as simian virus 40 (SV40), but is not required for MCV sT-induced rodent Cell transformation. We compared similarities and differences in PP2A binding between MCV and SV40 sT. While SV40 sT coimmunopurified with subunits PP2A Aα and PP2A C, MCV sT coimmunopurified with PP2A Aα, PP2A Aβ, and PP2A C. Scanning alanine mutagenesis at 29 sites across the MCV sT protein revealed that PP2A-binding domains lie on the opposite molecular surface from a previously described large T stabilization domain (LSD) loop that binds E3 ligases, such as Fbw7. MCV sT-PP2A interactions can be functionally distinguished by mutagenesis from MCV sT LSD-dependent 4E-BP1 hyperphosphorylation and viral DNA replication enhancement. MCV sT has a restricted range for PP2A B subunit substitution, inhibiting only the assembly of B56α into the phosphatase holoenzyme. In contrast, SV40 sT inhibits the assembly of B55α, B56α and B56e into PP2A. We conclude that MCV sT is required for Merkel Cell carcinoma growth, but its in vitro transforming activity depends on LSD interactions rather than PP2A targeting. IMPORTANCE Merkel Cell Polyomavirus is a newly discovered human cancer virus that promotes cancer, in part, through expression of its small T (sT) oncoprotein. Animal Polyomavirus sT oncoproteins have been found to cause experimental tumors by blocking the activities of a group of phosphatases called protein phosphatase 2A (PP2A). Our structural analysis reveals that MCV sT also displaces the B subunit of PP2A to inhibit PP2A activity. MCV sT, however, only displaces a restricted subset of PP2A B subunits, which is insufficient to cause tumor Cell formation in vitro . MCV sT instead transforms tumor Cells through another region called the large T stabilization domain. The PP2A targeting and transforming activities lie on opposite faces of the MCV sT molecule and can be genetically separated from each other.
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large t and small t antigens of Merkel Cell Polyomavirus
Current Opinion in Virology, 2015Co-Authors: J A Wendzicki, Patrick S Moore, Yuan ChangAbstract:Merkel Cell Polyomavirus (MCV) is the etiological agent of Merkel Cell carcinoma (MCC), a rare and highly lethal human skin cancer. A natural component of skin flora, MCV becomes tumorigenic only after integration into the host DNA together with specific mutations to the viral genome. Research on MCV large T (LT) and small T (sT) antigens, the only viral products expressed in MCC, shows that these major oncoproteins not only possess biochemical functions found in common with other Polyomavirus T antigens, but also demonstrate new Cellular targets not described in previous Polyomavirus models. This review provides a map of the relevant functional motifs and domains in MCV T antigens that have been identified, highlighting their roles in tumorigenesis.
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Merkel Cell Polyomavirus positive Merkel Cell carcinoma requires viral small t antigen for Cell proliferation
Journal of Investigative Dermatology, 2014Co-Authors: Masahiro Shuda, Yuan Chang, Patrick S MooreAbstract:To the Editor Angermeyer et al. (2013) claim that “Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma Cells Do Not Require Expression of the Viral Small T Antigen” (Angermeyer et al., 2013). This controversial conclusion is based on their inability to detect Merkel Cell Polyomavirus (MCV) small T (sT) protein expression and to inhibit Cell growth by putative sT knockdown in MCV-MCC Cells. These findings contradict existing evidence showing MCV sT protein expression in MCV-MCC cancer tissues (Shuda et al., 2011) and Cell lines (see Figure. 2, Houben et al., 2010) (Guastafierro et al., 2013). To investigate this discrepancy, we tried replicating Angermeyer et al's results using the same antibodies to detect MCV sT (CM8E6 (Kwunet al., 2009), CM5E1 (Shuda et al., 2011) and 2T2 ((Wang et al., 2012), kindly provided by C. Buck) on a panel of MCV-MCC Cell lines (Figure 1). MCV sT and large T (LT) are alternatively-spliced viral oncoproteins sharing a common N-terminus but having different C-termini, thus CM8E6 and 2T2 detects all isoforms of T antigens, while CM5E1 detects only sT and CM2B4 detects only LT and related isoforms. Differences in protein expression levels between MCV LT and sT are likely dependent on either premRNA or post-transcriptional protein processing. For positive and negative controls, we used UISO Cells transiently transfected with the MCV T antigen locus ({"type":"entrez-nucleotide","attrs":{"text":"JN038578","term_id":"354683949","term_text":"JN038578"}}JN038578) or with corresponding empty vector. UISO, commonly described as being from MCC origin (Houben et al., 2007), is negative for MCV and miRNA ontology studies show it clusters with Cell lines of breast cancer origin (Renwick et al., 2013). In contrast to Angermeyer et al., the 19 kD MCV sT band is readily detected in all MCV-MCC Cell lines (open arrows) but not in UISO Cells. Figure 1 Detection of Merkel Cell Polyomavirus (MCV) small T (sT) antigen expression by multiple MCV T antigen antibodies. Figure 2 Merkel Cell Polyomavirus (MCV) small T (sT) antigen knockdown inhibits MCV-positive Merkel Cell carcinoma (MCC) Cell proliferation.
Virve Koljonen - One of the best experts on this subject based on the ideXlab platform.
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Merkel Cell Polyomavirus is a passenger virus in both poroma and porocarcinoma
Journal of Cutaneous Pathology, 2021Co-Authors: Annastiina Merilainen, Harri Sihto, Virve KoljonenAbstract:Background Merkel Cell Polyomavirus (MCPyV) has been studied in several malignant and nonmalignant tissues. However, only in Merkel Cell carcinoma (MCC) has the connection to tumorigenesis been established. Previously, eccrine porocarcinoma samples were shown to express MCPyV in the majority of samples. We aimed to examine MCPyV in porocarcinoma and poroma samples using MCC as the reference material. Methods We analyzed 17 porocarcinoma and 50 poroma samples for the presence of MCPyV using LT antigen immunostaining and DNA detection methods. In addition, 180 MCC samples served as controls. Results MCPyV LT antigen immunostaining was detected in 10% of poroma and 18% of porocarcinoma samples; on the other hand, it was present in 65% of MCC samples. MCPyV DNA was detected in only 10% of poroma and porocarcinoma samples compared with 96% of MCC samples. The viral DNA copy number in all MCPyV DNA-positive MCCs was at least 25 times higher than that in porocarcinoma or poroma samples with the highest MCPyV DNA-to-PTPRG ratio. Conclusions The low number of viral DNA copies in poroma and porocarcinoma samples, together with the negative LT expression of MCPyV DNA-positive tumors, indicates that MCPyV is simply a passenger virus rather than an oncogenic driver of porocarcinoma.
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history of chronic inflammatory disorders increases the risk of Merkel Cell carcinoma but does not correlate with Merkel Cell Polyomavirus infection
British Journal of Cancer, 2017Co-Authors: Helka Sahi, Tom Böhling, Virve Koljonen, Harri Sihto, Miia Artama, Eero PukkalaAbstract:We aimed to assess the connection between chronic inflammatory disorders (CIDs) and Merkel Cell carcinoma (MCC). Merkel Cell carcinoma cases diagnosed in 1978–2009 were extracted from the Finnish Cancer Registry and controls from the Population Registry. Information on reimbursed CIDs was linked to clinicopathological data including Merkel Cell Polyomavirus (MCV) status by qPCR and immunohistochemistry for the large T antigen of MCV (LTA), Ki-67 and tumour-infiltrating lymphocytes. Chronic inflammatory disorders increased the risk of MCC significantly (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.03–1.88), specifically connective tissue/systemic diseases (OR 1.75, 95% CI 1.09–1.80) and diabetic conditions (OR 1.51, 95% CI 1.03–2.22). Chronic inflammatory disorders associated with larger tumour diameter (P=0.02) and higher Ki-67 expression (P=0.005). The expression of LTA was seen significantly more often in the absence of CIDs (P=0.05). Patients with CID are at significantly higher risk for aggressive MCC. Merkel Cell Polyomavirus positivity is more common in MCC patients unafflicted by CID.
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chronic lymphocytic leukaemia patients have a high risk of Merkel Cell Polyomavirus dna positive Merkel Cell carcinoma
British Journal of Cancer, 2009Co-Authors: Virve Koljonen, Heli Kukko, Risto Sankila, Tom Böhling, Erkki Tukiainen, Eero Pukkala, Harri Sihto, Heikki JoensuuAbstract:Chronic lymphocytic leukaemia patients have a high risk of Merkel-Cell Polyomavirus DNA-positive Merkel-Cell carcinoma
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chronic lymphocytic leukaemia patients have a high risk of Merkel Cell Polyomavirus dna positive Merkel Cell carcinoma
British Journal of Cancer, 2009Co-Authors: Virve Koljonen, Heli Kukko, Risto Sankila, Tom Böhling, Erkki Tukiainen, Eero Pukkala, Harri Sihto, Heikki JoensuuAbstract:Immunosuppression and Merkel-Cell Polyomavirus (MCPyV) infection may have a role in the pathogenesis of Merkel-Cell carcinoma (MCC), a rare neuroendocrine carcinoma of the skin. We studied incidence of chronic lymphocytic leukaemia (CLL) and MCC from the files of the Finnish Cancer Registry and the largest hospital of Finland, Helsinki University Central Hospital, from 1979 to 2006. Presence of MCPyV DNA in MCCs was investigated by quantitative PCR. We identified 4164 patients diagnosed with CLL and 172 diagnosed with MCC. Six patients diagnosed with both diseases were found; CLL was the first diagnosis in four cases and MCC in two. The standardised incidence ratio (SIR) for CLL after the diagnosis of MCC was highly elevated, 17.9 (95% confidence interval (CI), 2.2–64.6; P<0.001), and the SIR for MCC after the diagnosis of CLL was also elevated, 15.7 (3.2–46.0, P<0.01). Merkel-Cell Polyomavirus DNA was present in all five MCCs with tumour tissue available for analysis. We conclude that patients diagnosed with CLL have a substantially increased risk for MCC, and vice versa. Merkel-Cell Polyomavirus DNA is frequently present in MCCs that occur in CLL patients. Immunosuppression related with CLL and viral infection might explain the association between CLL and MCC.
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clinical factors associated with Merkel Cell Polyomavirus infection in Merkel Cell carcinoma
Journal of the National Cancer Institute, 2009Co-Authors: Harri Sihto, Heli Kukko, Risto Sankila, Tom Böhling, Virve Koljonen, Heikki JoensuuAbstract:BACKGROUND: Merkel Cell carcinoma is a rare malignancy of the skin. Integration of Merkel Cell Polyomavirus (MCPyV) DNA to the tumor genome is frequent in these cancers. The clinical consequences of MCPyV infection are unknown. METHODS: We analyzed formalin-fixed paraffin-embedded Merkel Cell carcinoma tissue samples from 114 of 207 patients diagnosed with Merkel Cell carcinoma in Finland from 1979 to 2004 for the presence of MCPyV DNA with the use of polymerase chain reaction (PCR), quantitative PCR, and DNA sequencing and examined associations between tumor MCPyV DNA status and histopathologic factors and survival. The median follow-up time after Merkel Cell carcinoma diagnosis for subjects who were alive was 9.9 years (range = 4.9-21.9 years). All P values are two-sided. RESULTS: MCPyV DNA was present in 91 carcinomas (79.8%). Compared with MCPyV DNA-negative cancers, MCPyV DNA-positive cancers were more often located in a limb (40.7% vs 8.7%, P = .015) and less frequent in patients who had regional nodal metastases at diagnosis (6.6% vs 21.7%, P = .043). Patients with MCPyV DNA-positive tumors had better overall survival than those with MCPyV DNA-negative tumors (5-year survival: 45.0% vs 13.0%, respectively; P < .001, two-sided log-rank test). CONCLUSIONS: MCPyV infection is associated with clinical outcomes in patients with Merkel Cell carcinoma. These findings lend support to the hypothesis that viral infection is frequently associated with the pathogenesis of Merkel Cell carcinoma.
Jianxin You - One of the best experts on this subject based on the ideXlab platform.
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Merkel Cell Polyomavirus and human Merkel Cell carcinoma
Recent results in cancer research, 2021Co-Authors: Wei Liu, Jianxin YouAbstract:Merkel Cell Polyomavirus (MCPyV) is the most recently discovered human oncogenic virus. MCPyV asymptomatically infects most of the human population. In the elderly and immunocompromised, however, it can cause a highly lethal form of human skin cancer called Merkel Cell carcinoma (MCC). Distinct from the productive MCPyV infection that replicates the viral genome as episomes, MCC tumors contain replication-incompetent, integrated viral genomes. Mutant MCPyV tumor antigen genes expressed from the integrated viral genomes are essential for driving the oncogenic development of MCPyV-associated MCC. In this chapter, we summarize recent discoveries on MCPyV virology, mechanisms of MCPyV-mediated oncogenesis, and the current therapeutic strategies for MCPyV-associated MCCs.
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Merkel Cell Polyomavirus a new dna virus associated with human cancer
Advances in Experimental Medicine and Biology, 2017Co-Authors: Margo Macdonald, Jianxin YouAbstract:Merkel Cell Polyomavirus (MCPyV or MCV) is a novel human Polyomavirus that has been discovered in Merkel Cell carcinoma (MCC), a highly aggressive skin cancer. MCPyV infection is widespread in the general population. MCPyV-associated MCC is one of the most aggressive skin cancers, killing more patients than other well-known cancers such as cutaneous T-Cell lymphoma and chronic myelogenous leukemia (CML). Currently, however, there is no effective drug for curing this cancer. The incidence of MCC has tripled over the past two decades. With the widespread infection of MCPyV and the increase in MCC diagnoses, it is critical to better understand the biology of MCPyV and its oncogenic potential. In this chapter, we summarize recent discoveries regarding MCPyV molecular virology, host Cellular tropism, mechanisms of MCPyV oncoprotein-mediated oncogenesis, and current therapeutic strategies for MCPyV-associated MCC. We also present epidemiological evidence for MCPyV infection in HIV patients and links between MCPyV and non-MCC human cancers.
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Merkel Cell Polyomavirus infection and Merkel Cell carcinoma.
Current opinion in virology, 2016Co-Authors: Wei Liu, Margo Macdonald, Jianxin YouAbstract:Merkel Cell Polyomavirus is the only Polyomavirus discovered to date that is associated with a human cancer. MCPyV infection is highly prevalent in the general population. Nearly all healthy adults asymptomatically shed MCPyV from their skin. However, in elderly and immunosuppressed individuals, the infection can lead to a lethal form of skin cancer, Merkel Cell carcinoma. In the last few years, new findings have established links between MCPyV infection, host immune response, and Merkel Cell carcinoma development. This review discusses these recent discoveries on how MCPyV interacts with host Cells to achieve persistent infection and, in the immunocompromised population, contributes to MCC development.
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identifying the target Cells and mechanisms of Merkel Cell Polyomavirus infection
Cell Host & Microbe, 2016Co-Authors: Wei Liu, Christopher B Buck, Rachel M Schowalter, Megan E Spurgeon, Paul F Lambert, Ruifeng Yang, Aimee S Payne, Jianxin YouAbstract:Summary Infection with Merkel Cell Polyomavirus (MCPyV) can lead to Merkel Cell carcinoma (MCC), a lethal form of skin cancer. However, the skin Cell type productively infected by MCPyV remains a central question. We combined Cell culture and ex vivo approaches to identify human dermal fibroblasts as natural host Cells that support productive MCPyV infection. Based on this, we established a Cell culture model for MCPyV infection, which will facilitate investigation of the oncogenic mechanisms for this DNA virus. Using this model, we discovered that induction of matrix metalloproteinase ( MMP ) genes by the WNT/β-catenin signaling pathway and other growth factors stimulates MCPyV infection. This suggests that MCC risk factors such as UV radiation and aging, which are known to stimulate WNT signaling and MMP expression, may promote viral infection and thus drive MCC. Our study also introduces the FDA-approved MEK antagonist trametinib as an effective inhibitor for controlling MCPyV infection.
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Merkel Cell Polyomavirus large t antigen disrupts host genomic integrity and inhibits Cellular proliferation
Journal of Virology, 2013Co-Authors: Xin Wang, Christopher B Buck, Jason Diaz, Sabrina H Tsang, Jianxin YouAbstract:ABSTRACT Clonal integration of Merkel Cell Polyomavirus (MCV) DNA into the host genome has been observed in at least 80% of Merkel Cell carcinoma (MCC). The integrated viral genome typically carries mutations that truncate the C-terminal DNA binding and helicase domains of the MCV large T antigen (LT), suggesting a selective pressure to remove this MCV LT region during tumor development. In this study, we show that MCV infection leads to the activation of host DNA damage responses (DDR). This activity was mapped to the C-terminal helicase-containing region of the MCV LT. The MCV LT-activated DNA damage kinases, in turn, led to enhanced p53 phosphorylation, upregulation of p53 downstream target genes, and Cell cycle arrest. Compared to the N-terminal MCV LT fragment that is usually preserved in mutants isolated from MCC tumors, full-length MCV LT shows a decreased potential to support Cellular proliferation, focus formation, and anchorage-independent Cell growth. These apparently antitumorigenic effects can be reversed by a dominant-negative p53 inhibitor. Our results demonstrate that MCV LT-induced DDR activates p53 pathway, leading to the inhibition of Cellular proliferation. This study reveals a key difference between MCV LT and simian vacuolating virus 40 LT, which activates a DDR but inhibits p53 function. This study also explains, in part, why truncation mutations that remove the MCV LT C-terminal region are necessary for the oncogenic progression of MCV-associated cancers.