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

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành hóa học dành cho các bạn yêu hóa học tham khảo 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 .