TLR4-Mediated Recognition of Mouse Polyomavirus Promotes Cancer-Associated Fibroblast-Like Phenotype and Cell Invasiveness

0542160 - ÚOCHB 2022 RIV CH eng J - Journal Article
Janovec, Václav - Ryabchenko, B. - Škarková, A. - Pokorná, Karolína - Rösel, D. - Brábek, J. - Weber, Jan - Forstová, J. - Hirsch, Ivan - Huérfano, S.
TLR4-Mediated Recognition of Mouse Polyomavirus Promotes Cancer-Associated Fibroblast-Like Phenotype and Cell Invasiveness.
Cancers (Basel). Roč. 13, č. 9 (2021), č. článku 2076. E-ISSN 2072-6694
Research Infrastructure: Czech-BioImaging II - 90129
Institutional support: RVO:61388963
Keywords : mouse polyomavirus * MPyV * mouse fibroblasts * CAF * TLR4 * IL-6 * spheroid invasiveness
OECD category: Virology
Impact factor: 6.575, year: 2021
Method of publishing: Open access
https://doi.org/10.3390/cancers13092076

The tumorigenic potential of mouse polyomavirus (MPyV) has been studied for decades in cell culture models and has been mainly attributed to nonstructural middle T antigen (MT), which acts as a scaffold signal adaptor, activates Src tyrosine kinases, and possesses transforming ability. We hypothesized that MPyV could also transform mouse cells independent of MT via a Toll-like receptor 4 (TLR4)-mediated inflammatory mechanism. To this end, we investigated the interaction of MPyV with TLR4 in mouse embryonic fibroblasts (MEFs) and 3T6 cells, resulting in secretion of interleukin 6 (IL-6), independent of active viral replication. TLR4 colocalized with MPyV capsid protein VP1 in MEFs. Neither TLR4 activation nor recombinant IL-6 inhibited MPyV replication in MEFs and 3T6 cells. MPyV induced STAT3 phosphorylation through both direct and MT-dependent and indirect and TLR4/IL-6-dependent mechanisms. We demonstrate that uninfected mouse fibroblasts exposed to the cytokine environment from MPyV-infected fibroblasts upregulated the expressions of MCP-1, CCL-5, and α-SMA. Moreover, the cytokine microenvironment increased the invasiveness of MEFs and CT26 carcinoma cells. Collectively, TLR4 recognition of MPyV induces a cytokine environment that promotes the cancer-associated fibroblast (CAF)-like phenotype in noninfected fibroblasts and increases cell invasiveness.
Permanent Link: http://hdl.handle.net/11104/0319640