Deficiency of DNA repair nuclease ERCC1-XPF promotes prostate cancer progression in a tissue recombination model.
Deficiency of DNA repair nuclease ERCC1-XPF promotes prostate cancer progression in a tissue recombination model.
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DOI：
10.1002/pros.22472
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发表时间：
2012-08-01
期刊：
影响因子：
2.8
通讯作者：
Bacich, Dean J.
中科院分区：
文献类型：
--
作者：
Matoka, Derek J.;Yao, Veronica;Harya, Diana S.;Gregg, Jennifer L.;Robinson, Andria R.;Niedernhofer, Laura J.;Parwani, Anil V.;Maier, Christoph;Bacich, Dean J.
The excision repair cross complementing (ERCC1) gene product plays a vital role in the nucleotide excision repair and DNA interstrand crosslink repair pathways, which protect the genome from mutations and chromosomal aberrations, respectively. Genetic deletion of Ercc1 in the mouse causes dramatically accelerated aging. We examined the effect of Ercc1 deletion in the development of prostate cancer in a prostate recapitulation model as Ercc1 deficient mice die within four weeks of birth. Prostate tissues from Ercc1−/− mice or wild-type littermates were combined with embryonic rat urogenital mesenchyme and grown as renal grafts for a total of 8, 16 and 24 weeks before histological, expression and proliferative evaluation. Invasive adenocarcinoma was observed in Ercc1−/− tissue recombinants but not wild-type as early as 8 weeks post-grafting. PIN-like lesions in Ercc1−/− tissue recombinants had more cytologic and architectural atypia than wild-type (p=0.02, p=0.0065 and p=0.0003 at the 8, 16 and 24 weeks respectively), as well as more proliferative cells (p=0.022 and p=0.033 at 8 and 16 weeks respectively). With serial grafting, Ercc1−/− tissue recombinants progressed to a more severe histopathological phenotype more rapidly than wild-type (p=0.011). Results show that ERCC1 and by implication the nucleotide excision repair and/or interstrand crosslink repair mechanisms protect against prostate carcinogenesis and mutations or polymorphisms affecting these DNA repair pathways may predispose prostate epithelial cells to transformation.
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