砷剂逆转非霍奇金淋巴瘤细胞SOCS1及SHP1基因甲基化作用机制

The prognosis of non-Hodgkin's lymphoma has been improved for the outcoming targeted drugs, however, that is not the same thing for refractory/recurrent NHL patients. It has been proved that the metylation in CpG region of SOCS1 and SHP1, which play an important role in JAK/STAT3 signaling pathway, is essential with the development and MDR in NHL. The traditional Chinese medicine has its own superiorities for the effection and deteimine the treatment basing on differentation of symptoms and signs. Our preliminary experiments have found that metylation could be detected with SOCS1 in several NHL cell lines. Furthermore, we conformed that arsenical could inhibit the proliferation of several kinds of NHL cell lines and induce that to apoptosis. However, the precisely mechanism of that is not clear. In order to investigate the methylation condition in NHL cells and the mechanism for arsenical to reverse the methylation, we aim to investigate deeply in three ways as follows: firstly, to build methylation gene library of NHL; secondly, to illustrate the mechanism for arsenical to reverse the metylation of SOCS1 and SHP1 and the regulation of JAK/STAT3 pathway; thirdly, we also try to investigate the mechanism of the above experiment in vivo. Our aim is to find the significance of metylation in the happeniss and development of NHL. Furthermore, we also try The JAK/STAT3 signaling pathway will also been studied here. Our aim is to provide the theoristic base for the application of arsenical in the treatment of NHL.

化疗及靶向治疗使非霍奇金淋巴瘤（NHL）的预后有所改善，但仍有约1/3的患者复发难治。已证实在JAK/STAT3信号通路中，SOCS1及SHP1基因启动子区的甲基化与NHL发病及耐药密切相关。传统中药因辨证施治、疗效确切而突显出优势。课题组前期研究证实在多种NHL细胞内，SOCS1基因发生明显甲基化，中药砷剂可抑制这些细胞的增殖并诱导其凋亡，但确切机制不清，且在不同细胞株内作用各异。为进一步探讨NHL细胞内甲基化状态及砷剂逆转甲基化的确切机制和作用形式，本研究拟进行以下方面的探讨：①构建NHL细胞内甲基化基因库；②阐明砷剂逆转SOCS1、SHP1基因甲基化的机制及JAK/STAT3信号通路的调控作用；③通过动物试验进一步验证砷剂逆转SOCS1、SHP1基因甲基化作用机制，最终揭示DNA甲基化在NHL发生、发展和耐药中的意义，为砷剂作为逆转甲基化有效药物发挥其治疗NHL的作用提供理论依据。

化疗及靶向治疗使非霍奇金淋巴瘤（NHL）的预后有所改善，但仍有1/3的患者复发难治。SOCS1及SHP1基因启动子区的甲基化及JAK/STAT3通路与NHL发病与耐药密切相关。传统中药因辨证施治、疗效确定而突显出优势。课题组前期研究证实在多种NHL细胞内，SOCS1基因发生明显甲基化，中药砷剂可抑制NHL细胞增殖并诱导其凋亡，但确切机制不清，且在不同细胞株内作用各异。为进一步探讨NHL细胞内甲基化状态及砷剂逆转甲基化的确切机制和作用形式，本研究在以下方面进行探讨：1.研究砷剂对非霍奇金淋巴瘤中基因甲基化的作用及调控机制；2. 检测NHL中新型甲基化基因的表达情况和分子调控机制；3. 进一步观察JAK/STAT3信号通路调控在多种NHL细胞增殖、凋亡、耐药中的作用及机制研究，为砷剂作为逆转甲基化有效药物发挥治疗NHL的作用提供理论依据。