| At present, gastric cancer still is one of the leading causes of cancer-related deaths worldwide, especially in developing countries.For the early diagnosis of the patient with effective bio-marker combined with clinical surgery have resulted in excellent long-term survival for patients with early cancer. Our project mainly presented from the following three parts, expounds the expression of TRIM59 in gastric carcinoma, and the biological mechanism of TRIM59 involved in the regulation of gastric carcinogenesis. TRIM59 was defined as a novel molecular target in the prognosis and treatment of gastric cancer, which can provide some help for clinical diagnosis and treatment.Part 1: We performed searches and a meta-analysis on microarray data sets from the Oncomine database(www.oncomine.com) for possible targets whose expressions are altered significantly in gastric cancer. Interestingly, TRIM59, which was located on chromosome 3, was the top hit found from many oncogene in our searches. TRIM59, with unidentified biological functions, was a novel TRIM gene family member. We report in this part that TRIM59 is up-regulated in gastric cancer and strongly associated with poor patient outcome. We further assessed the expression of TRIM59 in multiple gastric cancer cell lines, clinical samples and tissue array. We found that high mRNA and protein levels of TRIM59 in gastric cancer cell lines versus GES-1 and a significantly increased expression level of TRIM59 in gastric tumors versus normal tissues.Part 2: TRIM59 was knocked down and overexpressed in gastric cancer cell lines and the effects on proliferation, clone formation, migration, and growth of xenograft tumors in nude mice were assessed. TRIM59-related signaling pathways were examined by immunoblotting and quantitative PCR. We found that inhibition of TRIM59 leads to suppression of proliferation, clone formation, and migration of gastric cancer cell lines, as well as growth of xenograft tumors in nude mice while overexpression of TRIM59 had the opposite effects. TRIM59 knockdown suppressed the activation of several tumor related signaling pathway. Further more, we found a negative correlation between p53 and p53 downstream molecules.Part 3: We detected the half-life of p53 by ectopic expression of TRIM59 and analyzed interactions among TRIM59, p53 and ubiquitin in immunoprecipitation studies. We found that TRIM59 interacted physically with p53, increasing its ubiquitination and degradation by proteasome-mediated mechanisms. Then TRIM59 affect the transcriptional activity of p53 protein. Therefore, TRIM59 might promote gastric carcinogenesis via this mechanism.In conclusion, we found a novel gene TRIM59 which can serve as a prognois bio-marker predicted the development of patients’ cancer and our study has shown the biological and clinical significance of TRIM59 in gastric cancer. TRIM59 activated the related signaling pathways involved in tumor development and promoted the proliferation, clone formation, and migration of gastric cancer cell lines, as well as growth of xenograft tumors in nude mice. Finally, we found that TRIM59 exerts an inhibitory effect on p53 and its downstream signals via promoting p53 ubiquitination and degradation. TRIM59 might promote tumor growth and progression via this mechanism. Pharmaceutical intervention in the interaction between TRIM59 and p53 may provide a promising strategy to reactivate p53 signaling in gastric cancer patients with wildtype p53. |
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