title: Up-regulation of the embryonic self-renewal network through reversible polyploidy in irradiated p53-mutant tumour cells.
abstract: We have previously documented that transient polyploidy is a potential cell survival strategy underlying the clonogenic re-growth of tumour cells after genotoxic treatment. In an attempt to better define this mechanism, we recently documented the key role of meiotic genes in regulating the DNA repair and return of the endopolyploid tumour cells (ETC) to diploidy through reduction divisions after irradiation. Here, we studied the role of the pluripotency and self-renewal stem cell genes NANOG, OCT4 and SOX2 in this polyploidy-dependent survival mechanism. In irradiation-resistant p53-mutated lymphoma cell-lines (Namalwa and WI-L2-NS) but not sensitive p53 wild-type counterparts (TK6), low background expression of OCT4 and NANOG was up-regulated by ionising radiation with protein accumulation evident in ETC as detected by OCT4/DNA flow cytometry and immunofluorescence (IF). IF analysis also showed that the ETC generate PML bodies that appear to concentrate OCT4, NANOG and SOX2 proteins, which extend into complex nuclear networks. These polyploid tumour cells resist apoptosis, overcome cellular senescence and undergo bi- and multi-polar divisions transmitting the up-regulated OCT4, NANOG and SOX2 self-renewal cassette to their descendents. Altogether, our observations indicate that irradiation-induced ETC up-regulate key components of germ-line cells, which potentially facilitate survival and propagation of the tumour cell population.
authors.affiliation: Latvian Biomedical Research and Study Centre, Riga, LV-1067, Latvia. kristine@biomed.lu.lv
authors.forename: Kristine
authors.initials: K
authors.lastname: Salmina
authors.forename: Eriks
authors.initials: E
authors.lastname: Jankevics
authors.forename: Anda
authors.initials: A
authors.lastname: Huna
authors.forename: Dmitry
authors.initials: D
authors.lastname: Perminov
authors.forename: Ilze
authors.initials: I
authors.lastname: Radovica
authors.forename: Tetyana
authors.initials: T
authors.lastname: Klymenko
authors.forename: Andrey
authors.initials: A
authors.lastname: Ivanov
authors.forename: Elina
authors.initials: E
authors.lastname: Jascenko
authors.forename: Harry
authors.initials: H
authors.lastname: Scherthan
authors.forename: Mark
authors.initials: M
authors.lastname: Cragg
authors.forename: Jekaterina
authors.initials: J
authors.lastname: Erenpreisa
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D009154:Mutation / Q000235:genetics; D000071317:Nanog Homeobox Protein; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D050814:Octamer Transcription Factor-3 / Q000235:genetics*; D011123:Polyploidy; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53