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 high-LET nature, energetic iron ions are expected to pose greater CRC risks to astronauts undertaking long duration space missions beyond low earth orbit (LEO). Wild-type p53-induced phosphatase 1 (Wip1) is important for cellular DNA damage response and its abrogation is reported to inhibit spontaneous intestinal tumorigenesis in APCMin/+ mice, a well-studied mouse model of human CRC. However, Wip1 in relation to radiation-induced especially energetic iron ions-induced intestinal tumorigenesis has not been investigated in APCMin/+ mice. While we earlier demonstrated greater intestinal tumorigenic potential of energetic iron ions relative to 137Cs γ rays, the purpose of the current study was to investigate if Wip1 abrogation could influence radiation quality dependent intestinal tumorigenesis in APCMin/+ mice. Intestinal tumor frequency and grade was 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 irradiated and sham irradiated mice. Decreased tumor frequency and lower tumor grade was observed in APCMin/+;Wip1−/− relative to APCMin/+;Wip1+/+ mice. Notably, similar decrease (~6 fold in both groups) in tumor number was observed in sham-, and γ-irradiated APCMin/+;Wip1−/− relative to APCMin/+;Wip1+/+ mice. However, tumorigenesis in energetic iron ions group was reduced ~8 fold in APCMin/+;Wip1−/− relative to APCMin/+;Wip1+/+ mice. Significantly lower proliferation/differentiation index in tumors of energetic iron ions exposed APCMin/+;Wip1−/− relative to APCMin/+;Wip1+/+ mice suggests reduced proliferation and enhanced differentiation as a result of Wip1 abrogation. In conclusion, the current study demonstrates that the absence of Wip1 could block radiation-induced intestinal tumorigenesis irrespective of radiation quality and has implications for developing preventive strategies against tumorigenic potential of radiation exposure on earth and in outer space.

Genomic Instability and Carcinogenesis of Heavy Charged Particles Radiation: Clinical and Environmental Implications

“…By contrast, irradiation with high LET radiations causes massive DNA damage and lethal effects, leading to reduced possibility of DNA repair [14]. The inhibition of DNA damage responses (DDRs) can improve the efficiency of heavy charged particles in suppressing tumor regression [15].…”

Space radiation exposure persistently increased leptin and IGF1 in serum and activated leptin-IGF1 signaling axis in mouse intestine

“…The goal is to acquire in vivo biological data in animal models for development of risk models, which NASA will be able to use for prediction of risk to human during long duration space missions. While more studies are required to develop a clear understanding of tissue-specific effects of 56 Fe radiation, we have published a series of peer-reviewed original research papers on heavy ion exposure-associated GI tissue effects using CRC mouse model as well as wild type mice 3 4 5 10 11 12 13 14 15 . In the current study, we investigated leptin and IGF1 signaling due to our observation of increased obesity-related factors such as body weight, serum triglyceride and insulin, and peroxisome proliferator-activated receptor γ (PPARγ) after 56 Fe radiation.…”

Colorectal Carcinogenesis, Radiation Quality, and the Ubiquitin-Proteasome Pathway

“…Our results on intestinal tumorigenesis in APC Min/+ with Wip1 (wild-type p53 induced phosphatase-1) knockout (APC Min/+ ; Wip1 -/- ) mice showed that Wip1 abrogation abolishes radiation-induced intestinal tumorigenesis in these mice 122 . Since, Wip1, a phosphatase, is a radiation responsive protein known to regulate the p53-MDM2 auto-regulatory loop through dephosphorylation of p53 and dephosphorylated p53 is subjected to MDM2 mediated ubiquitination and its subsequent degradation via proteasome 123 , abrogation of Wip1 is believed to allow p53 accumulation and thus block tumorigenesis.…”