lncRNA HIMETA正反馈调节HIF信号通路促进乳腺癌侵袭转移的分子机制研究

The aberrant expression or function of Long non-coding RNAs (lncRNAs) can lead to the occurrence of many diseases including cancer. Our preliminary data showed that lncRNA HIMETA is significantly up-regulated in breast cancer tissue compared with adjacent normal tissue, and high expression level of lncRNA HIMETA correlate with longer survival in patients. We found the expression of lncRNA HIMETA can be directly activated by HIF signaling pathway, and the inhibition of the expression of HIMETA suppress the migration and invasion of breast cancer cell lines. We further found that HIMETA may upregulate the protein expression level of HIF-1α through directly interact with it. The above preliminary data indicate that HIMETA may promote the migration of breast cancer through the positive feedback regulation of HIF signaling pathway. Our present study aims to reveal: 1) how does HIMETA up-regulate the protein level of HIF-1α through interacting with it; 2) the role of HIMETA-HIF-1α complex in the regulation of the breast cancer migration; 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, and provide novel molecular targets for therapies against breast cancers.

长链非编码RNA（lncRNA）的表达或功能异常与包括肿瘤在内的多种疾病密切相关。申请人在前期研究中发现lncRNA HIMETA在乳腺癌中异常高表达，并且其表达水平高低与病人预后相关。我们发现HIMETA的表达受到HIF信号通路的直接激活，沉默其表达后能显著抑制乳腺癌细胞系的迁移和侵袭。进一步研究发现HIMETA可能通过与HIF-1α的相互作用来提高其蛋白表达水平。我们的前期研究结果提示HIMETA可能通过正反馈调节HIF信号通路来促进乳腺癌侵袭转移。本项目拟在前期研究基础上阐明：1）HIMETA如何通过结合HIF-1α来提高其蛋白表达水平；2）HIMETA-HIF-1α复合体在乳腺癌转移调控中的作用；3）HIMETA在乳腺癌中异常高表达的原因及其用于临床诊断和治疗靶点的价值。本项目的开展有助于揭示乳腺癌侵袭转移调控新机制，并为转移乳腺癌的治疗提供潜在新靶点。

lncRNA是一种重要的乳腺癌调控基因。经过本项目的研究，我们证实了lncRNA HIMETA在乳腺癌中异常高表达，并且高表达与乳腺癌病人差的预后显著相关。体内外实验证实敲低lncRNA HIMETA能够抑制乳腺上皮细胞发生EMT和转移，推测它可能通过抑制肿瘤细胞的转移来影响患者预后。机制上，我们发现lncRNA HIMETA在低氧下可通过与PKM2互作来促进HIF1A的转录，从而增强乳腺癌细胞的转移能力，促进乳腺癌转移的发生。此外，我们还发现lncRNA HIMETA能翻译出我们成为METABRAKE的小肽，在低氧下具有能抑制lncRNA HIMETA促转移功能的能力。以上部分内容本人以第一或通讯作者（含共同）的身份在Cell，Nucleic Acids Res，Nature communications等杂志上发表5篇论文，后续工作还获得广东省杰出青年科学基金的资助。本项目还有部分研究还在进行当中，预计在近期能够发表更多的高水平论文。