组织局部的酸性微环境是恶性肿瘤的生物学特征之一。我们前期工作显示乳腺癌细胞在酸性微环境中通过ASIC1-ROS-NF-κB通路促进了乳腺癌的侵袭、转移，但对NF-κB（p65）的入核调控机制并不清楚。LncRNA芯片分析显示，酸性条件下乳腺癌细胞中Lnc-MALAT1表达显著上升，敲除MALAT1则抑制了p65入核；此外，NF-κB通路激活也正反馈促进了MALAT1的表达。根据前述工作基础，我们提出“酸性微环境ASIC1—ROS—NF-κB信号通路依赖MALAT1促进乳腺癌侵袭转移”的假说。为了证实该假说，本项目拟研究：1.酸性微环境下MALAT1通过增强p65与importinα亲和力促进p65入核的机制；2.激活NF-κB 对MALAT1表达的正反馈机制；3.通过转基因小鼠模型及临床标本检测评价MALAT1及ASIC1在乳腺癌中的临床预后判断及靶向治疗价值，为乳腺癌的防治提供新的思路。

The extracellular low pH microenvironment is one of the most prominent features of solid tumor, which due to the high glycolysis and poor perfusion within tumors. Our previous work found the activation of ASIC1-ROS-NFκB pathway play a vital role in progression and metastasis of breast cancer, but the detail mechanism of NF-κB (p65) nuclear import still remained unclear. LncRNA chip analysis of the breast cancer cell revealed that the expression of Lnc-MALAT1 was highly increased under acidosis cell culture, while knock-out of MALAT1 suppressed nuclear import of p65 and then inactivated NF-κB pathway; furthermore, it seems like a positive feedback that the activation of NF-κB potentiate the expression of MALAT1 as well. Based on the above evidence, we proposed a hypothesis that under extracellular acidosis environment, the ASIC1—ROS—NF-κB pathway depending on MALAT1 facilitated the invasiveness of breast cancer. To prove this hypothesis, several experiments were carried out as following:1. To identify the mutual binding point of MALAT1 and p65; 2. To verify the impact of MALAT1 on the binding affinity between p65 and importinα; 3. To evaluate the clinical and prognostic value of MALAT1 and ASIC1 in breast cancer via transgenic mice model and multi-center cancer specimens. Our program intends to clarifies the molecular function of MALAT1 in breast cancer under acidosis microenvironment, and provide further scientific basis for targeting therapy towards ASIC1 and MALAT1 in breast cancer.