研究发现长链非编码RNA参与调控诸多病理生理过程，然而对其认识尚处于初期阶段。其中长链非编码RNA H19已被证实在肿瘤等多种疾病中发挥重要作用，我们已发表的研究证实H19可通过H19/SAHH/DNMT3B信号通路影响DNA甲基化，进一步研究其分子机制及其临床应用的可行性具有重要意义。本项目预实验发现H19可下调自噬关键基因Beclin-1甲基化诱导自噬，从而降低乳腺癌细胞他莫昔芬耐药株对他莫昔芬的敏感性，但具体调控机制不明。本项目拟从细胞、动物和临床组织三个层面探索验证：(1)H19是否通过影响自噬参与乳腺癌他莫昔芬耐药；(2)H19/SAHH/DNMT3B信号通路是否下调Beclin-1甲基化进而影响自噬；(3)H19是否可预测他莫昔芬耐药。本项目旨在揭示一个新的乳腺癌他莫昔芬耐药机制，阐明H19在其中的作用，为乳腺癌他莫昔芬耐药的临床诊治、预后判断及药物筛选提供新的靶点。

Long non-coding RNAs have been proved to constitute an additional layer controlling the cellular pathophysiological process. Among them, lncRNA H19 is a critical player in many diseases, including cancer. Our previous published study has already demonstrated the critical roles of H19/SAHH/DNMT3B axis in regulating DNA methylation. Our preliminary data showed that long noncoding RNA H19 might decrease the sensitivity of Tamoxifen resistant breast cancer cell to Tamoxifen treatment. Besides, we demonstrated that H19 was involved in autophagy process via down-regulating the promoter methylation status of Beclin-1. We proposed a novel mechanism of Tamoxifen resistance: H19 decreases the sensitivity of breast cancer to Tamoxifen via down-regulating methylation status of Beclin-1 and inducing autophagy. In vitro and in vivo experiments will be utilized: (1)To investigate whether H19 is involved in Tamoxifen resistance through influencing autophagy; (2) To explore the effects of H19/SAHH/DNMT3B pathway on the promoter methylation status of Beclin-1 and autophagy; (3)To reveal the predictive value of H19 for Tamoxifen resistance. Our study aims to reveal a novel mechanism of Tamoxifen resistance, to illustrate the molecular mechanism of H19 in Tamoxifen resistance and to provide the novel biomarkers for predicting and intervention of Tamoxifen resistance.