Involvement of ubiquitination and sumoylation in bladder lesions induced by persistent long-term low dose ionizing radiation in humans.
OBJECTIVE
We determined whether ubiquitination and sumoylation processes are up-regulated in bladder urothelium by chronic, long-term, persistent low doses of ionizing radiation in male patients with benign prostate hyperplasia and females with chronic cystitis living more than 19 years in 137Cs contaminated areas after the Chernobyl accident in Ukraine.


METHODS
Bladder urothelial biopsies from 45 patients were subjected to histopathological and immunohistochemical study of Ub, SUMO1, SUMO E2 conjugating enzyme Ubc9, and the cell cycle inhibitors p53 and p27(Kip1).


RESULTS
Of 25 group 1 patients from radio contaminated areas chronic proliferative atypical cystitis (Chernobyl cystitis), featuring multiple foci of dysplasia, and carcinoma in situ were observed in 23 (92%) and 19 (76%), respectively, in addition to 1 small pTa grade 1 urothelial carcinoma. Chronic cystitis with areas of dysplasia and urothelial hyperplasia were detected in 2 (10%) and 3 (15%), respectively of the 20 patients in control group 2 from clean (without radio contamination) areas of Ukraine. Greatly increased levels of Ub, SUMO1, Ubc9 and p53 as well as decreased levels of p27(Kip1) were evident in patients in group 1 compared to those in group 2 (all p <0.001).


CONCLUSIONS
These findings support the hypothesis that up-regulated ubiquitination and sumoylation processes might be an adaptive response to unscheduled proteolysis of aberrant p53 and p27(Kip1) cell cycle regulators occurring with long-term low dose rate ionizing radiation exposure with a possible contribution to urothelial carcinogenesis.
Romanenko
Alina M
AM
Department of Pathology, Institute of Urology, Academy of Medical Sciences of Ukraine, Ukraine.
Kinoshita
Anna
A
Wanibuchi
Hideki
H
Wei
Min
M
Zaparin
Wadim K
WK
Vinnichenko
Wladimir I
WI
Vozianov
Alexander F
AF
Fukushima
Shoji
S
D000368:Aged; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis / Q000378:metabolism*; D003556:Cystitis / Q000378:metabolism*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011832:Radiation Injuries / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000032:analysis / Q000378:metabolism*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism*; D025801:Ubiquitin / Q000032:analysis / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000032:analysis / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000032:analysis / Q000378:metabolism*; D001743:Urinary Bladder / Q000737:chemistry / Q000473:pathology*; D000098843:Ubiquitin-Conjugating Enzyme UBC9
C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D025842:SUMO-1 Protein; D016159:Tumor Suppressor Protein p53; C470301:UBA2 protein, human; D025801:Ubiquitin; D050760:Cyclin-Dependent Kinase Inhibitor p27; D044763:Ubiquitin-Conjugating Enzymes; D044764:Ubiquitin-Activating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9