Up-regulation of the embryonic self-renewal network through reversible polyploidy in irradiated p53-mutant tumour cells.
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.
Salmina
Kristine
K
Latvian Biomedical Research and Study Centre, Riga, LV-1067, Latvia. kristine@biomed.lu.lv
Jankevics
Eriks
E
Huna
Anda
A
Perminov
Dmitry
D
Radovica
Ilze
I
Klymenko
Tetyana
T
Ivanov
Andrey
A
Jascenko
Elina
E
Scherthan
Harry
H
Cragg
Mark
M
Erenpreisa
Jekaterina
J
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
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