tailieunhanh - báo cáo hóa học:" Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer"

Tuyển tập các báo cáo nghiên cứu về hóa học được đăng trên tạp chí sinh học đề tài : Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer | Fujisawa et al. Journal of Translational Medicine 2011 9 37 http content 9 1 37 JOURNAL OF TRANSLATIONAL MEDICINE RESEARCH Open Access Histone modification enhances the effectiveness of IL-13 receptor targeted immunotoxin in murine models of human pancreatic cancer Toshio Fujisawa Bharat H Joshi and Raj K Puri Abstract Background Interleukin-13 Receptor a2 IL-13Ra2 is a tumor-associated antigen and target for cancer therapy. Since IL-13Ra2 is heterogeneously overexpressed in a variety of human cancers it would be highly desirable to uniformly upregulate IL-13Ra2 expression in tumors for optimal targeting. Methods We examined epigenetic regulation of IL-13Ra2 in a murine model of human pancreatic cancer by Bisulfite-PCR sequencing for DNA methylation and chromatin immunoprecipitation for histone modification. Reverse transcription-PCR was performed for examining changes in IL-13Ra2 mRNA expression after treatment with histone deacetylase HDAC and c-jun inhibitors. In vitro cytotoxicity assays and in vivo testing in animal tumor models were performed to determine whether HDAC inhibitors could enhance anti-tumor effects of IL-13-PE in pancreatic cancer. Mice harboring subcutaneous tumors were treated with HDAC inhibitors systemically and IL-13-PE intratumorally. Results We found that CpG sites in IL-13Ra2 promoter region were not methylated in all pancreatic cancer cell lines studied including IL-13Ra2-positive and IL-13Ra2-negative cell lines and normal cells. On the other hand histones at IL-13Ra2 promoter region were highly-acetylated in IL-13Ra2-positive but much less in receptornegative pancreatic cancer cell lines. When cells were treated with HDAC inhibitors not only histone acetylation but also IL-13Ra2 expression was dramatically enhanced in receptor-negative pancreatic cancer cells. In contrast HDAC inhibition did not increase IL-13Ra2 in normal cell lines. In addition c-jun in IL-13Ra2-positive cells was expressed at higher .