ATPIF1促进三阴性乳腺癌转移的机制研究

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high frequency of metastasis and the absence of effective target therapy. Using comparative proteomics approach, we identified that mitochondrial protein ATPase inhibitory factor 1 (ATPIF1) was highly expressed in metastatic TNBC tissues, compared with non-metastatic ones. In vitro and in vivo studies indicated that ATPIF1 could promote the migration and invasion of TNBC cells through activating PTEN/AKT/mTOR/HIF-1α signaling pathway. Moreover, we identified that ATPIF1 was transcriptionally activated by HIF-1α. Based on these findings, we hypothesize that the upregulation of ATPIF1 could facilitate PTEN/AKT/mTOR/HIF-1α signaling pathway, and HIF-1α in turn mediates the transcription of ATPIF1, leading to the formation of a positive feedback loop and accelerates TNBC metastasis. Firstly, we will clarify the effect of ATPIF1 on the energy metabolism of TNBC cells and investigate the molecular mechanisms underlying reciprocal regulation between ATPIF1 and HIF-1α. Secondly, we will confirm enforced expression of ATPIF1 in TNBC cells strengthen their capacity to develop distal pulmonary metastases in vivo and investigate the influence of the positive feedback loop between ATPIF1 and HIF-1α on TNBC metastasis. Finally, we will analyze the correlation of ATPIF1 and TNBC patients’ prognosis via tissue chips. Our research project may help gain novel insights into the mechanisms underlying TNBC metastasis, and provide new treatment options.

三阴性乳腺癌（TNBC）是极易转移的乳腺癌亚型，缺乏有效的靶向治疗。课题组通过比较蛋白质组学发现ATP酶抑制因子1（ATPIF1）在转移组TNBC中高表达；体内外实验表明ATPIF1可通过激活PTEN/AKT/mTOR/HIF-1α通路促进TNBC的转移；且HIF-1α可转录活化ATPIF1的表达。基于此，课题组提出假说：在TNBC中ATPIF1高表达可激活PTEN/AKT/mTOR/HIF-1α通路，HIF-1α活化后转录活化ATPIF1，从而形成正反馈机制促进TNBC的转移。课题组拟首先在分子层面阐明ATPIF1对TNBC细胞能量代谢的影响以及和HIF-1α相互调节的机制；并分析上述正反馈通路对TNBC转移的影响；在裸鼠实验中验证ATPIF1促进TNBC的转移；最后通过组织芯片分析ATPIF1与TNBC患者预后的相关性。研究结果将有助于阐明TNBC新的转移机制，并为其治疗提供新的思路。

三阴性乳腺癌（TNBC）是极易转移的乳腺癌亚型，缺乏有效的靶向治疗。课题组通过比较蛋白质组学发现ATP酶抑制因子1（ATPIF1）在转移组TNBC中高表达；体内外实验表明ATPIF1可通过激活PTEN/AKT/mTOR/HIF-1α通路促进TNBC的转移；且HIF-1α可转录活化ATPIF1的表达。基于此，课题组提出假说：在TNBC中ATPIF1高表达可激活PTEN/AKT/mTOR/HIF-1α通路，HIF-1α活化后转录活化ATPIF1，从而形成正反馈机制促进TNBC的转移。首先，我们课题组在分子层面阐明ATPIF1对TNBC细胞能量代谢的影响以及和HIF-1α相互调节的机制；并分析上述正反馈通路对TNBC转移的影响；研究结果显示在TNBC中，ATPIF1表达受缺氧微环境表达上调，并且ATPIF1促进缺氧诱导的HIF-1α表达改变。ATPIF1基因启动子上存在潜在的HIF-1α结合位点，干预HIF-1α表达及活性均可以明显抑制TNBC细胞中ATPIF1的表达。然后我们通过裸鼠肺转移模型也验证了ATPIF1促进TNBC的转移；最后我们通过组织芯片分析得出ATPIF1高表达与TNBC患者预后差显著相关。本研究将有助于阐明TNBC新的转移机制，并为其治疗提供新的思路。这些研究结果不仅能更深入的了解TNBC能量代谢和肿瘤转移的相互调节机制，同时有助于理解这些机制在TNBC转移和预后中的作用，并为抗癌药物的设计提供新的作用靶点。