DPT通过PI3K/Akt通路调节NHE1介导酸性微环境促进乳腺癌脑转移的机制研究

脑转移发生影响乳腺癌患者预后。NHE1介导的酸性微环境在乳腺癌转移中起到关键作用，而调控NHE1介导酸性微环境促进脑转移的上游机制尚不明确。前期工作发现在脑转移癌中DPT表达远低于原发乳腺癌或其他器官转移中的表达，其相关基因富集PI3K/Akt信号通路在脑转移中被激活，并调控NHE1表达。据此提出假设DPT通过PI3K/Akt通路调节NHE1介导酸性微环境促进乳腺癌脑转移。本项目拟收集临床样本验证DPT表达与乳腺癌脑转移的相关性及特异性。在细胞及动物模型中，研究DPT表达与乳腺癌的颅内转移瘤形成、脑转移瘤侵袭、PI3K/Akt通路表达、NHE1激活水平的相互关系。探索DPT通过PI3K/Akt信号通路调控NHE1表达促进脑转移形成的作用机制。本项目研究成果为明确乳腺癌脑转移颅内成瘤的发病机制提供新的证据，也为脑转移癌的治疗策略和治疗药物提供新的靶点，具有重要的学术价值和应用价值。

Brain metastasis seriously affects the prognosis of breast cancer patients. NHE1-mediated acidic microenvironment plays a key role in breast cancer brain metastasis, and the upstream mechanism of regulating NHE1-mediated acidic microenvironment to promote brain metastasis is still unclear. Previous work found that the expression of DPT in brain metastatic tumors was much lower than that in primary breast cancer or other organ metastasis. PI3K/Akt signaling pathway enriched by related genes was activated in brain metastasis and regulated the expression of NHE1. It was hypothesized that DPT regulates the NHE1-mediated acidic microenvironment through the PI3K/Akt pathway to promote brain metastasis in breast cancer. This project intends to collect clinical samples to verify the correlation between DPT expression and clinical, indicators such as clinical classification, prognosis, molecular subtype, and brain metastasis. In cell and animal models, the relationship of DPT expression, brain metastatic formation, tumor invasion, PI3K/Akt pathway expression level, or NHE1 activation level was investigated. To explore the mechanism by which DPT regulates NHE1 expression via the PI3K/Akt signaling pathway and affects the formation of brain metastasis. The results of this project provide new evidence for the pathogenesis of brain metastatic intracranial tumorigenesis of breast cancer and also provide new targets for the treatment strategies and therapeutic drugs of brain metastatic cancer, which have important academic and application values.