title: Wip1 abrogation decreases intestinal tumor frequency in APC(Min/+) mice irrespective of radiation quality.
abstract: Low-linear energy transfer (low-LET) γ-ray exposure is a risk factor for colorectal cancer (CRC). Due to their high-LET nature, energetic iron ions found in space are expected to pose greater CRC risks to astronauts undertaking long-duration space missions beyond low Earth orbit. Wild-type p53-induced phosphatase 1 (Wip1) is important for cellular DNA damage response and its abrogation has been shown to inhibit spontaneous intestinal tumorigenesis in APC(Min/+) mice, a well-studied mouse model of human CRC. However, the relationship of Wip1 to radiation-induced intestinal tumorigenesis, especially by energetic iron ions, has not been investigated in APC(Min/+) mice. We have previously reported that there is a greater intestinal tumorigenic potential of iron-ion radiation relative to (137)Cs γ rays, so the purpose of the current study was to investigate whether Wip1 abrogation could influence high-LET dependent intestinal tumorigenesis in APC(Min/+) mice. Intestinal tumor frequency and grade were assessed in APC(Min/+)/Wip1(-/-) mice and results were compared to those in APC(Min/+)/Wip1(+/+) mice after exposure to a mean absorbed dose of 2 Gy from (137)Cs γ rays or 1.6 Gy from 1 GeV/n iron ions. Cellular differentiation and proliferation were also assessed in the intestinal tumors of sham-irradiated and irradiated mice. Decreased tumor frequency and lower tumor grade were observed in APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice. Notably, a similar decrease (∼6-fold in both groups) in tumor number was observed in sham-irradiated and γ-irradiated APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice. However, tumorigenesis in the energetic iron-ion exposed group was reduced ∼8-fold in APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice. A significantly lower proliferation/differentiation index in tumors of iron-ion exposed APC(Min/+)/Wip1(-/-) relative to APC(Min/+)/Wip1(+/+) mice suggests that reduced proliferation and enhanced differentiation as a result of Wip1 abrogation maybe involved. In conclusion, the current study demonstrated that the absence of Wip1 blocked radiation-induced intestinal tumorigenesis irrespective of radiation quality and has implications for developing preventive strategies against the tumorigenic potential of radiation exposure on earth and in outer space.
authors.affiliation: a  Department of Biochemistry and Molecular and Cellular Biology and Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057.
authors.forename: Shubhankar
authors.initials: S
authors.lastname: Suman
authors.forename: Bo-Hyun
authors.initials: BH
authors.lastname: Moon
authors.forename: Hemang
authors.initials: H
authors.lastname: Thakor
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.forename: Kamal
authors.initials: K
authors.lastname: Datta
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D005260:Female; D017491:Genes, APC; D007414:Intestinal Neoplasms / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000209:etiology*; D010749:Phosphoprotein Phosphatases / Q000502:physiology*; D000071636:Protein Phosphatase 2C
chemical_list: C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C