Cancers, Vol. 11, Pages 1260: CRISPR/Cas9 Editing of the Polyomavirus Tumor Antigens Inhibits Merkel Cell Carcinoma Growth In Vitro

Cancers, Vol. 11, Pages 1260: CRISPR/Cas9 Editing of the Polyomavirus Tumor Antigens Inhibits Merkel Cell Carcinoma Growth In Vitro Cancers doi: 10.3390/cancers11091260 Authors: Arturo Temblador Dimitrios Topalis Graciela Andrei Robert Snoeck Merkel cell carcinoma (MCC) is an aggressive type of skin cancer whose main causative agent is Merkel cell polyomavirus (MCPyV). MCPyV is integrated into the genome of the tumor cells in most MCCs. Virus-positive tumor cells constitutively express two viral oncoproteins that promote cell growth: the small (sT) and the large (LT) tumor antigens (TAs). Despite the success of immunotherapies in patients with MCC, not all individuals respond to these treatments. Therefore, new therapeutic options continue to be investigated. Herein, we used CRISPR/Cas9 to target the viral oncogenes in two virus-positive MCC cell lines: MS-1 and WAGA. Frameshift mutations introduced in the target sequence upon repair of the Cas9-induced DNA break resulted in decreased LT protein levels, which subsequently impaired cell proliferation, caused cell cycle arrest, and led to increased apoptosis. Importantly, a virus-negative non-MCC cell line (HEK293T) remained unaffected, as well as those cells expressing a non-targeting single-guide RNA (sgRNA). Thus, we presumed that the noted effects were not due to the off-target activity of the TAs-targeting sgRNAs. Additionally, WAGA cells had altered levels of cellular proteins involved in cell cycle regulati...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research

Related Links:

This article provides a structured literature review of the most important studies investigating the role of PET or PET/CT in the clinical practice of MCC.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Merkel cell carcinoma (MCC) is a rare, highly aggressive skin cancer for which immune modulation by immune checkpoint inhibitors show remarkable response rates. However, primary or secondary resistance to immunotherapy prevents benefits in a significant proportion of patients. For MCC, one immune escape mechanism is insufficient recognition by T cells due to downregulation of major histocompatibility complex (MHC) class I surface expression. Histone deacetylase (HDAC) inhibitors have been demonstrated to epigenetically reverse low MHC class I expression caused by downregulation of the antigen processing machinery (APM).
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Original Article Source Type: research
You Polyomavirus infection is widespread in the human population. This family of viruses normally maintains latent infection within the host cell but can cause a range of human pathologies, especially in immunocompromised individuals. Among several known pathogenic human polyomaviruses, JC polyomavirus (JCPyV) has the potential to cause the demyelinating disease progressive multifocal leukoencephalopathy (PML); BK polyomavirus (BKPyV) can cause nephropathy in kidney transplant recipients, and Merkel cell polyomavirus (MCPyV) is associated with a highly aggressive form of skin cancer, Merkel cell carcinoma (MCC). While ...
Source: Viruses - Category: Virology Authors: Tags: Review Source Type: research
Conclusion: Considering the important role of the LT-Ag in the pathogenicity of MCPyV, non-synonymous mutations compared with the reference proteins triggered relevant amino acid substitutions. Overall, the results showed no tumor-associated mutations in the LT-Ag sequence of MCPyVs from positive samples.Public Health Genomics
Source: Public Health Genomics - Category: Genetics & Stem Cells Source Type: research
We thank Testori et  al. [1] for their letter to the Editor related to our published European consensus-based interdisciplinary guidelines on the diagnosis and treatment of basal cell carcinoma (BCC) [2]. They comment on the role of electrochemotherapy (ECT) as ‘an adjunctive treatment for basal cell carcinoma’ an d state that omission of mentioning ECT in the management of patients with BCC in our guidelines should be corrected with a formal addendum [1]. They underline that a short paragraph about ECT was included in the EADO guidelines on Kaposi sarcoma, Merkel cell carcinoma and cutaneous squamous cell ca rcinoma (SCC).
Source: European Journal of Cancer - Category: Cancer & Oncology Authors: Tags: Author's reply Source Type: research
In this study, we show that MURs are necessary for regulating LT stability via multiple E3 ligase interactions, resulting in cell growth arrest. While expression of wild-type MCV LT induced a decrease in cellular proliferation, deletion of the MUR domains resulted in increased LT stability and cell proliferation. Conversely, addition of MURs to SV40 LT propagated E3 ligase interactions, which in turn, reduced SV40 LT stability and decreased cell growth activity. Our results demonstrate that compared to other human polyomaviruses (HPyVs), MCV LT has evolved to acquire the MUR domains that are essential for MCV LT autoregula...
Source: Viruses - Category: Virology Authors: Tags: Article Source Type: research
Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Conventionally fractionated post-operative radiotherapy (cPORT) is associated with improved locoregional control but is also associated with increased time on treatment, late skin toxicities, and wound healing issues.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Source Type: research
In conclusion, our report suggests that MCPyV TA contribute to the acquisition of an MC-like phenotype in epithelial cells.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
ConclusionsFemale gender, tumor-free resection margins, and local disease were found to be independent prognostic factors in MCC progression. Patients with hematological malignancies, immunosuppression, and those with immune deficiencies should be closely followed up as they are predisposed to develop MCC.
Source: Dermatology and Therapy - Category: Dermatology Source Type: research
Abstract Merkel cell carcinoma (MCC) is an aggressive skin cancer with high rates of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases. MCPyV-induced tumourigenesis is largely dependent on the expression of the small tumour antigen (ST). Recent findings implicate MCPyV ST expression in the highly metastatic nature of MCC by promoting cell motility and migration, through differential expression of cellular proteins that lead to microtubule destabilisation, filopodium formation and breakdown of cell-cell junctions. However, the molecular mechanisms which dysregu...
Source: The Biochemical Journal - Category: Biochemistry Authors: Tags: Biochem J Source Type: research
More News: Cancer | Cancer & Oncology | Carcinoma | Gastroschisis Repair | Immunotherapy | Merkel Cell Carcinoma | Skin | Skin Cancer