Abstract
BackgroundIodine 125 (125I) seed irradiation can be used as an important supplementary treatment for unresectable advanced gastric cancer. Here, we aim to comprehensively elucidate the biological effects induced by 125I seed irradiation in human gastric cancer xenograft model by using global expression and DNA methylation analyses.MethodsThe 48 mice bearing NCI-N87 gastric cancer xenografts were randomly separated into 2 groups: sham seeds (O mCi) were implanted into the control group (n = 24); 125 l seeds (0.9 mCi) were implanted into the treatment group (n = 24). The mitotic index and apoptotic index were evaluated by quantitative morphometric analysis of the expression of proliferating cell nuclear antigen (PCNA) and in situ terminal transferase-mediated fluorescein deoxy- UTP nick end labeling (TUNEL), respectively. Global gene expression changes induced by 125I seed irradiation were analyzed by using Nimblegen Human gene expression array. DNA methylation profile in the tumors from control group was investigated with methylated DNA immunoprecipitation (MeDIP) and Nimblegen CpG promoter microarrays. The changes in the methylation status of selected genes were further investigated by using MeDIP-PCR.Results125I seed irradiation suppresses the growth of gastric cancer xenografts in nude mice. PCNA staining and tissue TUNEL assays showed that both inhibition of cell proliferation and induction of apoptosis contribute to the 125I-induced tumor suppression in nude mouse model. Gene expression profiles revealed that the expression levels of several hundred genes, many of which are associated with apoptosis or cell cycle arrest, including BMF, MAPK8, BNIP3, RFWD3, CDKN2B and WNT9A, were upregulated following 125I seed irradiation. Furthermore, the up-regulation of some of these genes, such as BNIP3 and WNT9A, was found to be associated with irradiation-induced DNA demethylation.ConclusionsThis study revealed that 125I seed irradiation could significantly induce the up-regulation of apoptosis- and cell cycle-related genes in human gastric cancer xenografts. And some of the up-regulation might be attributed to 125I-irradiation induced demethylation in gene promoter regions. Collectively, these findings provided evidence for the efficacy of this modality for the treatment of gastric cancer.
Highlights
Iodine 125 (125I) seed irradiation can be used as an important supplementary treatment for unresectable advanced gastric cancer
The effectiveness of 125I seed irradiation to inhibit the growth of implanted NCI-N87 tumors was examined in nude mouse model
The body weights of mice were not affected by the 125I irradiation and no obvious radiation-induced damage was observed in vital organs of mice, indicating the safety of 125I seed treatment
Summary
Iodine 125 (125I) seed irradiation can be used as an important supplementary treatment for unresectable advanced gastric cancer. We aim to comprehensively elucidate the biological effects induced by 125I seed irradiation in human gastric cancer xenograft model by using global expression and DNA methylation analyses. Surgery offers the only realistic chance of cure; many of the patients present with unresectable tumors at the time of diagnosis. 125I implantation has been widely used to treat prostate cancer and other tumor types because of its ability to offer high precision, little trauma, strong lethality, and fewer complications [6,7,8,9]. Wang and colleagues applied 125I implantation to treat advanced gastric cancer and found significant improvement in clinical symptoms and life quality of patients [10]
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