Merkel cell polyomavirus T antigens promote cell proliferation and inflammatory cytokine gene expression

Abstract

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 tumourderived 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.

Identifying the Target Cells and Mechanisms of Merkel Cell Polyomavirus Infection

“…The dysregulated MMP gene expression that supports MCPyV infection could also contribute to the virus-induced oncogenesis. Interestingly, a recent study from the Chang and Moore laboratory discovered that several MMP genes are induced in cells expressing T antigens derived from MCC tumors(Richards et al, 2015), which may further promote metastasis of MCPyV-induced MCC tumors.…”

Dissection of Merkel cell formation in hairy and glabrous skin reveals a common requirement for FGFR2‐mediated signalling

“…Future studies on the morphogenesis of Merkel cells are important not only for our understanding of the biology of the skin as a sensory organ but also for uncovering processes that lead to human pathologies. Hyper‐ or hypo‐sensitivity to touch have long been reported in patients with diabetes, inflammation or autism . Recent studies have shown that Merkel cells can inhibit alloknesis, a disease state where mechanical light touch stimuli provoke itching .…”

RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells

“…Indeed, knockdown of RB1 led in the tested MCPyV-positive MCC cell lines to a rescue of LT-knockdown-induced E2F target gene repression and more importantly, to a reversion of LT-knockdown-induced cell growth inhibition. The importance of the RB1-LT interaction is further sustained by a recent report: revealing that the overwhelming majority of MCPyV-LT induced gene expression alterations require the intact LxCxE binding motif [50]. …”