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 APCMin/ 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 APCMin/ mice. We have previously reported that there is a greater intestinal tumorigenic potential of iron-ion radiation relative to 137Cs γ rays, so the purpose of the current study was to investigate whether Wip1 abrogation could influence high-LET dependent intestinal tumorigenesis in APCMin/ mice. Intestinal tumor frequency and grade were assessed in APCMin/ /Wip1–/– mice and results were compared to those in APCMin/ /Wip1 / mice after exposure to a mean absorbed dose of 2 Gy from 137Cs 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 APCMin/ /Wip1–/– relative to APCMin/ /Wip1 / mice. Notably, a similar decrease (∼6-fold in both groups) in tumor number was observed in sham-irradiated and γ-irradiated APCMin/ /Wip1–/– relative to APCMin/ /Wip1 / mice. However, tumorigenesis in the energetic iron-ion exposed group was reduced ∼8-fold in APCMin/ /Wip1–/– relative to APCMin/ /Wip1 / mice. A significantly lower proliferation/differentiation index in tumors of iron-ion exposed APCMin/ /Wip1–/– relative to APCMin/ /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.
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Vol. 182 • No. 3