lncRNA ERBC通过结合FUBP1和KHSRP调控乳腺癌侵袭转移的分子机制研究

Long non-coding RNAs (lncRNAs) regulate the biological processes through interacting with proteins. The aberrant expression or function of lncRNAs can lead to the occurrence of many diseases including cancer. Our preliminary data showed that lncRNA ERBC is significantly down-regulated in breast cancer tissue compared with adjacent normal tissue, and low expression level of lncRNA ERBC correlate with shorter survival of patients. Moreover, lncRNA ERBC expressed at a lower level in breast cancer tissue of patients with lymph node metastasis than that of patients without lymph node metastasis, indicating that lncRNA ERBC might be involved in the regulation of breast cancer metastasis. We further found that lncRNA ERBC regulate the EMT of breast cancer cell line through inhibiting the expression of Snail by interacting with FUBP1 and KHSRP. Our present study aims to study: 1) the molecular mechanism of the interaction of lncRNA ERBC with FUBP1 and KHSRP; 2) how the RNA protein complex formed by lncRNA ERBC, FUBP1 and KHSRP regulate the metastasis of breast cancer; 3) the mechanism of aberrant expression of lncRNA ERBC in breast cancer and its value in the diagnosis and therapy of breast cancer. Our study will reveal a new mechanism beneath the metastasis of breast cancer, ann provide novel molecular targets for therapies against breast cancers.

长链非编码RNA（lncRNA）通过与蛋白相互作用来调节细胞生物学特性，其表达或功能异常与包括肿瘤在内的多种疾病相关。申请人在前期研究中发现lncRNA ERBC在乳腺癌中异常低表达，并且表达水平高低与病人预后相关。我们还发现lncRNA ERBC的表达在发生淋巴结转移的乳腺癌病人肿瘤组织中显著下调，提示lncRNA ERBC可能参与乳腺癌转移调控。进一步研究发现lncRNA ERBC通过与FUBP1和KHSRP蛋白的相互作用影响Snail蛋白的表达来调控乳腺癌细胞的EMT。本项目拟在前期研究基础上阐明：1）lncRNA ERBC调控FUBP1和KHSRP功能的机理研究；2）它们所形成的RNA-蛋白复合体与乳腺癌侵袭转移的关系；3）lncRNA ERBC在乳腺癌中异常下调的原因及其用于临床诊断和治疗的价值。本项目的开展有助于揭示乳腺癌侵袭转移调控的新机制，并为靶向治疗肿瘤的策略提供新靶点。

lncRNA是一种重要的乳腺癌调控基因。本项目发现并证实了lncRNA ERBC在乳腺癌中低异常低表达，并且低表与乳腺癌病人好的预后显著相关。敲低lncRNA ERBC能够促进乳腺上皮细胞发生EMT，推测它可能通过抑制肿瘤细胞的转移来影响患者预后。进一步我们发现lncRNA ERBC是通过促进TGFβ信号通路负调控因子smurf2的表达进而抑制TGFβ信号通路的，这一过程由lncRNA ERBC结合蛋白KHSRP介导。以上部分内容本人以第一作者身份发表在BBA-Mol Cell Res（IF：4.105）。本项目在研究lncRNA ERBC和RNA结合蛋白（RBP）KHSRP相互作用促进肿瘤发生发展过程中还系统鉴定了大量肿瘤相关RBP，该工作以第一作者鉴并列通讯作者身份发表在Nucleic Acids Res（IF：11.502）。本人同时还分析了乳腺癌病人化疗后肿瘤微环境的变化，证明了B细胞的多样性对化疗反应起到关键作用，对新型抗癌疗法的设计具有重要指导意义，该工作本人以并列第一作者排第三身份发表在了Cell（IF：38.637）上。为了研究lncRNA可能的RNA靶标，本研究还开发了高通量靶向RNA靶标组测序技术——CIRDES，该技术为进一步探索lncRNA特别是lncRNA ERBC奠定了基础，该工作本人以并列通讯作者身份发表在Analyst（IF：3.978）上。本人还分析了lncRNA的m6A修饰，发现包括lncRNA ERBC在内的大量lncRNA都有m6A修饰，并且这些m6A修饰的改变参与了细胞对低氧等逆境抵抗的调控，该工作本人以并列通讯作者身份发表在RNA Biology（IF：5.35）杂志上。