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PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

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DÖRSAM, Bastian, Nina SEIWERT, Sebastian FOERSCH, Svenja STROH, Georg NAGEL, Diana BEGALIEW, Erika DIEHL, Anna STIER, Aswin MANGERICH, Jörg FAHRER, 2018. PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression. In: Proceedings of the National Academy of Sciences of the United States of America. 115(17), pp. E4061-E4070. ISSN 0027-8424. eISSN 1091-6490. Available under: doi: 10.1073/pnas.1712345115

@article{Dorsam2018-04-24PARP1-42141, title={PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression}, year={2018}, doi={10.1073/pnas.1712345115}, number={17}, volume={115}, issn={0027-8424}, journal={Proceedings of the National Academy of Sciences of the United States of America}, pages={E4061--E4070}, author={Dörsam, Bastian and Seiwert, Nina and Foersch, Sebastian and Stroh, Svenja and Nagel, Georg and Begaliew, Diana and Diehl, Erika and Stier, Anna and Mangerich, Aswin and Fahrer, Jörg} }

Nagel, Georg Diehl, Erika Foersch, Sebastian Fahrer, Jörg Mangerich, Aswin Colorectal cancer (CRC) is one of the most common tumor entities, which is causally linked to DNA repair defects and inflammatory bowel disease (IBD). Here, we studied the role of the DNA repair protein poly(ADP-ribose) polymerase-1 (PARP-1) in CRC. Tissue microarray analysis revealed PARP-1 overexpression in human CRC, correlating with disease progression. To elucidate its function in CRC, PARP-1 deficient (PARP-1<sup>−/−</sup>) and wild-type animals (WT) were subjected to azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. Miniendoscopy showed significantly more tumors in WT than in PARP-1<sup>−/−</sup> mice. Although the lack of PARP-1 moderately increased DNA damage, both genotypes exhibited comparable levels of AOM-induced autophagy and cell death. Interestingly, miniendoscopy revealed a higher AOM/DSS-triggered intestinal inflammation in WT animals, which was associated with increased levels of innate immune cells and proinflammatory cytokines. Tumors in WT animals were more aggressive, showing higher levels of STAT3 activation and cyclin D1 up-regulation. PARP-1<sup>−/−</sup> animals were then crossed with O<sup>6</sup>-methylguanine-DNA methyltransferase (MGMT)-deficient animals hypersensitive to AOM. Intriguingly, PARP-1<sup>−/−</sup>/MGMT<sup>−/−</sup> double knockout (DKO) mice developed more, but much smaller tumors than MGMT<sup>−/−</sup> animals. In contrast to MGMT-deficient mice, DKO animals showed strongly reduced AOM-dependent colonic cell death despite similar O<sup>6</sup>-methylguanine levels. Studies with PARP-1<sup>−/−</sup> cells provided evidence for increased alkylation-induced DNA strand break formation when MGMT was inhibited, suggesting a role of PARP-1 in the response to O<sup>6</sup>-methylguanine adducts. Our findings reveal PARP-1 as a double-edged sword in colorectal carcinogenesis, which suppresses tumor initiation following DNA alkylation in a MGMT-dependent manner, but promotes inflammation-driven tumor progression. Diehl, Erika Dörsam, Bastian 2018-04-24 Stroh, Svenja Seiwert, Nina Nagel, Georg Mangerich, Aswin Stier, Anna eng Begaliew, Diana Foersch, Sebastian Fahrer, Jörg Dörsam, Bastian Stroh, Svenja Begaliew, Diana 2018-04-23T13:56:08Z PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression Seiwert, Nina Stier, Anna 2018-04-23T13:56:08Z

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