title: An intact retinoblastoma protein-binding site in Merkel cell polyomavirus large T antigen is required for promoting growth of Merkel cell carcinoma cells.
abstract: Merkel cell carcinoma (MCC) is a highly aggressive skin cancer that frequently harbours Merkel cell polyomavirus (MCV) DNA integrated in the genome of the tumor cells. In our study, we elaborate our recent finding that MCV-positive MCC cell lines require the expression of the viral T antigens (TA). Indeed, in a xeno-transplantation model, we prove that TA expression is essential also in an in vivo situation, as knock down of TA leads to tumor regression. Moreover, rescuing TA short hairpin RNA (shRNA)-treated MCV-positive MCC cells by ectopic expression of shRNA-insensitive TAs clearly demonstrates that the observed effect is caused by TA knockdown. Notably, introduction of a mutation in the LTA protein interfering with LTA binding to the retinoblastoma protein (RB) ablated this rescue. The importance of this interaction was further confirmed as LTA-specific knockdown leads to explicit cell growth inhibition. In summary, the presented data demonstrate that established MCV-positive MCC tumors critically depend on TA expression, in particular the LTA and RB interaction, for sustained tumor growth. Consequently, interference with LTA/RB interaction appears as promising strategy to treat MCC.
authors.affiliation: Department of Dermatology, University Hospital Würzburg, Würzburg, Germany. houben_r@klinik.uni-wuerzburg.de
authors.forename: Roland
authors.initials: R
authors.lastname: Houben
authors.forename: Christian
authors.initials: C
authors.lastname: Adam
authors.forename: Anne
authors.initials: A
authors.lastname: Baeurle
authors.forename: Sonja
authors.initials: S
authors.lastname: Hesbacher
authors.forename: Johannes
authors.initials: J
authors.lastname: Grimm
authors.forename: Sabrina
authors.initials: S
authors.lastname: Angermeyer
authors.forename: Katharina
authors.initials: K
authors.lastname: Henzel
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hauser
authors.forename: Roland
authors.initials: R
authors.lastname: Elling
authors.forename: Eva-B
authors.initials: EB
authors.lastname: Bröcker
authors.forename: Stefan
authors.initials: S
authors.lastname: Gaubatz
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Becker
authors.forename: David
authors.initials: D
authors.lastname: Schrama
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000502:physiology*; D001665:Binding Sites; D015266:Carcinoma, Merkel Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004318:Doxycycline / Q000494:pharmacology; D006801:Humans; D059965:Merkel cell polyomavirus / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D010641:Phenotype; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012878:Skin Neoplasms / Q000473:pathology*
chemical_list: D000952:Antigens, Polyomavirus Transforming; D016160:Retinoblastoma Protein; D004318:Doxycycline