title: ICAD deficiency in human colon cancer and predisposition to colon tumorigenesis: linkage to apoptosis resistance and genomic instability.
abstract: We previously showed that DNA fragmentation factor, which comprises a caspase-3-activated DNase (CAD) and its inhibitor (ICAD), may influence the rate of cell death by generating PARP-1-activating DNA breaks. Here we tested the hypothesis that ICAD-deficient colon epithelial cells exhibiting resistance to death stimuli may accumulate additional genetic modifications, leading to a tumorigenic phenotype. We show that ICAD deficiency may be associated with colon malignancy in humans. Indeed, an examination of ICAD expression using immunohistochemistry in an array of both colon cancer and normal tissues revealed that ICAD expression levels were severely compromised in the cancerous tissues. Upon DNA damage caused by a low dose of irradiation, ICAD cells acquire a tumorigenic phenotype. Colon epithelial cells derived from ICAD mice showed a significant resistance to death induced by the colon carcinogen dimethylhydrazine in vitro and in mice. Such resistance was associated with a decrease in PARP-1 activation. In an animal model of dimethylhydrazine-induced colon tumorigenesis, ICAD(-/-) mice developed significantly higher numbers of tumors with markedly larger sizes than the wild-type counterparts. Interestingly, the phenotype of the ICAD(-/-) mice was not associated with a significant increase in the precancerous aberrant crypt foci suggesting a potential link to tumor progression rather than initiation. More importantly, ICAD deficiency was associated with severe genomic instability as assessed by array comparative genomic hybridization. Such genomic instability consisted most prominently of amplifications but with sizable deletions as compared to the wild-type counterparts affecting several cancer-related genes including RAF-1, GSN, LMO3, and Fzd6 independently of p53. Altogether, our results present a viable case for the involvement of ICAD deficiency in colon carcinogenesis and show that apoptosis and genomic instability may comprise the means by which such deficiency may contribute to the process of increasing susceptibility to carcinogen-induced tumorigenesis.
authors: The Stanley Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors: Youssef
authors: Y
authors: Errami
authors: Hassan
authors: H
authors: Brim
authors: Karine
authors: K
authors: Oumouna-Benachour
authors: Mustapha
authors: M
authors: Oumouna
authors: Amarjit S
authors: AS
authors: Naura
authors: Hogyoung
authors: H
authors: Kim
authors: Jihang
authors: J
authors: Ju
authors: Christian J
authors: CJ
authors: Davis
authors: Jong G
authors: JG
authors: Kim
authors: Hassan
authors: H
authors: Ashktorab
authors: Kenneth
authors: K
authors: Fallon
authors: Ming
authors: M
authors: Xu
authors: Jianhua
authors: J
authors: Zhang
authors: Luis
authors: L
authors: Del Valle
authors: A Hamid
authors: AH
authors: Boulares
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D003106:Colon / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D003851:Deoxyribonucleases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism
chemical_list: C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D003851:Deoxyribonucleases; C109663:caspase-activated deoxyribonuclease