Jun Zhu1, Lianlian Tian2, Huichen Li3, Jun Hao4, Shuai Wang1, Jipeng Li1, Jian Zhang3. 1. State Key Laboratory of Cancer Biology, Institute of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. 2. Department of Pediatrics, Tangdu Hospital, Air Force Medical University, Xi'an, China. 3. State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, China. 4. Department of Experiment Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Abstract
BACKGROUND: Radiation-induced gastrointestinal syndrome (GIS) often occurs after therapeutic or accidental exposure to high doses of radiation. Unfortunately, there are still no effective medical treatments for GIS. N-Myc downstream regulated gene 2 (NDRG2), is a tumor suppressor gene and promotes cell apoptosis and differentiation. The aim of our study was to identify the role of NDRG2 in the progression of GIS and explore the potential mechanism. METHODS: We generated Ndrg2ΔG mice, lacking NDRG2 specifically in the intestinal epithelium. Survival analysis was performed to validate the effect of NDRG2 on GIS, and other common indicators (body weight loss and diarrhea) were used for the assessment of GIS. Enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) were conducted to obtain the expression of pro-inflammatory interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α). TUNNEL and western blotting were further adopted to determine the relationship between NDRG2 and apoptosis. Finally, we performed histology and immunohistochemistry assays to explore the morphological alternations and changes of proliferation-related molecules, including Ki-67 and proliferating cell nuclear antigen (PCNA). RESULTS: We found that after 8 gray of total body ɤ-irradiation (TBI), the deletion of NDRG2 in the intestine revealed longer survival time, considerably milder symptoms of GIS, and milder damage to jejunal tissue, compared with the WT mice. Moreover, the Ndrg2ΔG mice significantly inhibited the expression of pro-inflammatory IL-1β, IL-6, and TNF-α, which were typically increased by irradiation. Apoptosis of the epithelial cells in the Ndrg2ΔG mice was significantly milder while the ratio of proliferation cells was larger in the epithelium of mice 8 days after TBI when compared with the WT mice. CONCLUSIONS: These findings all indicated that NDRG2 deficiency in the intestine protects mice against radiation-induced GIS mainly through promoting proliferation and suppressing apoptosis of epithelial cells. 2021 Journal of Gastrointestinal Oncology. All rights reserved.
BACKGROUND: Radiation-induced gastrointestinal syndrome (GIS) often occurs after therapeutic or accidental exposure to high doses of radiation. Unfortunately, there are still no effective medical treatments for GIS. N-Myc downstream regulated gene 2 (NDRG2), is a tumor suppressor gene and promotes cell apoptosis and differentiation. The aim of our study was to identify the role of NDRG2 in the progression of GIS and explore the potential mechanism. METHODS: We generated Ndrg2ΔG mice, lacking NDRG2 specifically in the intestinal epithelium. Survival analysis was performed to validate the effect of NDRG2 on GIS, and other common indicators (body weight loss and diarrhea) were used for the assessment of GIS. Enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) were conducted to obtain the expression of pro-inflammatory interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha (TNF-α). TUNNEL and western blotting were further adopted to determine the relationship between NDRG2 and apoptosis. Finally, we performed histology and immunohistochemistry assays to explore the morphological alternations and changes of proliferation-related molecules, including Ki-67 and proliferating cell nuclear antigen (PCNA). RESULTS: We found that after 8 gray of total body ɤ-irradiation (TBI), the deletion of NDRG2 in the intestine revealed longer survival time, considerably milder symptoms of GIS, and milder damage to jejunal tissue, compared with the WT mice. Moreover, the Ndrg2ΔG mice significantly inhibited the expression of pro-inflammatory IL-1β, IL-6, and TNF-α, which were typically increased by irradiation. Apoptosis of the epithelial cells in the Ndrg2ΔG mice was significantly milder while the ratio of proliferation cells was larger in the epithelium of mice 8 days after TBI when compared with the WT mice. CONCLUSIONS: These findings all indicated that NDRG2 deficiency in the intestine protects mice against radiation-induced GIS mainly through promoting proliferation and suppressing apoptosis of epithelial cells. 2021 Journal of Gastrointestinal Oncology. All rights reserved.
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