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Fbxw7 haploinsufficiency loses its protection against DNA damage and accelerates MNU-induced gastric carcinogenesis
Yannan Jiang1, Xinming Qi2, Xinyu Liu1
1Department of Surgery of Shanghai Ruijin Hospital, Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Abstract:
Fbxw7, a subunit of the SCF E3 ubiquitin ligase, recognizes oncoprotein substrates and leads to their proteasomal degradation. Fbxw7 acts as a tumor suppressor via inducing apoptosis and growth arrest in various kinds of tumors. To clarify the initiating role in gastric carcinogenesis as well as the histologic characterization of tumor in Fbxw7 allele haploinsufficient mice, we generated Fbxw7 heterozygous knockout mice (Fbxw7+/-) and treated them with chemical carcinogen N-methyl-N-nitrosourea (MNU) at 5-6 weeks of age. We also treated mouse embryo fibroblasts (MEFs) from Fbxw7+/- and Fbxw7+/+ mice with MNU and examined cell DNA damage via comet assay. The protein expression of Fbxw7 and its substrate c-Myc from mouse tumors, as well as human tumors sampled from six patients, were detected by Western blot. As results, the tumor incidence was obviously higher in Fbxw7+/- mice (13/20) than in Fbxw7+/+ mice (6/20) after 35-week observation. Intestinal metaplasia (P = 0.013) and dysplasia (P = 0.036) were more severe in Fbxw7+/- mice than in Fbxw7+/+ mice. The repair potential of DNA damage was suppressed in MEFs from Fbxw7+/- mice after MNU exposure. Increased c-Myc expression was accompanied by decreased Fbxw7 protein expression in tumor tissues from mouse and patients. In conclusion, Fbxw7 haploinsufficiency increased the risk of gastric carcinogenesis induced by MNU, which is associated with the accumulation of DNA damage as well as c-Myc oncoprotein.
Insights
Fbxw7 haploinsufficiency accelerates gastric cancer in mice exposed to MNU. This is linked to impaired DNA repair and elevated c-Myc oncoprotein levels, highlighting Fbxw7
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Fbxw7, a component of the SCF E3 ubiquitin ligase complex, targets oncoproteins for degradation, functioning as a tumor suppressor.
- Fbxw7 deficiency is implicated in various cancers, but its specific role in initiating gastric carcinogenesis requires further elucidation.
Purpose of the Study:
- To investigate the role of Fbxw7 haploinsufficiency in gastric carcinogenesis induced by N-methyl-N-nitrosourea (MNU).
- To characterize the histological features of tumors in Fbxw7 heterozygous knockout mice.
- To examine the impact of Fbxw7 deficiency on DNA damage repair and c-Myc expression.
Main Methods:
- Generation of Fbxw7 heterozygous knockout (Fbxw7+/-) mice and treatment with MNU.
- Treatment of mouse embryo fibroblasts (MEFs) from Fbxw7+/- and Fbxw7+/+ mice with MNU, followed by comet assay for DNA damage.
- Western blot analysis of Fbxw7 and c-Myc protein expression in mouse and human tumor tissues.
Main Results:
- Fbxw7+/- mice exhibited significantly higher tumor incidence (13/20 vs. 6/20) compared to wild-type mice after MNU treatment.
- More severe intestinal metaplasia and dysplasia were observed in Fbxw7+/- mice.
- MEFs from Fbxw7+/- mice showed suppressed DNA damage repair capacity post-MNU exposure.
- Tumor tissues displayed decreased Fbxw7 and increased c-Myc protein levels.
Conclusions:
- Fbxw7 haploinsufficiency exacerbates MNU-induced gastric carcinogenesis in mice.
- This increased susceptibility is associated with impaired DNA damage repair and accumulation of the c-Myc oncoprotein.
- Findings suggest Fbxw7 plays a critical role in suppressing gastric tumor initiation.