全新长链非编码RNA-IRAIN异常印记转换和表观遗传失控在乳腺癌中的意义及作用机理

项目名称： 全新长链非编码RNA-IRAIN异常印记转换和表观遗传失控在乳腺癌中的意义及作用机理

项目编号： No.81502277

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 康丽花

作者单位： 吉林大学

项目金额： 18万元

中文摘要： 乳腺癌严重威胁女性健康，具有高度异质性。寻找以个体生物学为基础的治疗靶点成为提供个体化治疗及改善预后的关键。类胰岛素生长因1受体（IGF-1R）信号转导通路涉及乳腺癌的发生、发展、化疗耐药以及HER-2靶向治疗耐药等多方面。申请人导师采用R3C方法国际上首次在IGF-1R基因区发现一条全新的反义长链非编码RNA，命名为IRAIN。本人前期工作中首次发现乳腺癌组织中发生异常的等位基因印记转换现象，并提示IRAIN可能是抑癌基因，那么印记转换很可能是抑癌基因失活的一种全新的方式。本课题将深入研究IRAIN 印记转换的发生特点、临床意义和表观遗传学不稳定性；探讨IRAIN下游作用靶点及对乳腺癌生长及转移等生物学特性的影响；分析IRAIN 和乳腺癌临床因素及预后的相关性。将为肿瘤性疾病机制研究提供新的思路，为寻找对乳腺癌有预测、预后价值的生物标记物及个体化的乳腺癌治疗靶点提供理论基础和实验依据。

中文关键词： 乳腺肿瘤；长链非编码RNA；等位基因印记转换

英文摘要： Breast cancer is a highly heterogeneous disease which greatly threatens women's health, so finding out the biology-based target is becoming the key point to individualized treatment and better prognosis. The insulin-like growth factor 1 receptor (IGF-1R) pathway plays a critical role in initiation and progression of breast cancer, resistance to chemotherapy or HER-2 target therapy. Supervisor of the applicant firstly use a R3C method to identify the presence of a novel antisense long non-coding RNA (lncRNA).This lncRNA is imprinted expressed in normal tissue but expressed reversely with IGF-1R, it is thus named as IRAIN (IGF-1 receptor antisense imprinted non-coding RNA) .There is no report on IRAIN regulating IGF-1R expression. During my preliminary work, I firstly observe an IRAIN allele-switch epigenetic abnormality in breast tumour specimens. In normal tissues, IRAIN lncRNA is expressed from a parental allele. However, in breast cancer tissues, the expression of IRAIN lncRNA switches to the alternative parental allele. Preliminary data also suggested that IRAIN may be a tumor suppressor gene, then allele-switch is likely to be a new way of tumor suppressor gene inactivation.This project is proposed to address several issues: 1.How is the characteristics of IRAIN allele-switch, clinical significance and epigenetic instability? 2. What is the mechanism for the IGF-1R pathway regulation and which is the downstream target? 3. How does IRAIN work to affect breast cancer development and prognosis? In conclusion, this project will not only provide a new way to study the mechanism of tumor diseases,but also provide a mechanistic rationale for finding predicting biological marker for breast cancer and designing antitumor drugs that target the over-expressed IGF1R in breast cancer.

英文关键词： breast cancer ;long non-coding RNA;allele switch