低氧是影响实体肿瘤恶性进展的重要体内环境因子。肿瘤干细胞（CSC）是导致肿瘤转移、耐药、复发的根本。前期研究发现低氧下HIFα敲除的三阴性乳腺癌（TNBC）体现出HIF1α依赖的侵袭、CSC富集及基因、LncRNA表达特性；生物信息分析测序结果揭示3个新LncRNA协同调控Hippo信号可能参与CSC干性维持、转移。干预其中一个LncRNA表达，降低CSC干性与侵袭。推测这些HIF1α依赖的LncRNA调控TNBC-CSC干性与转移。该项目拟进一步采用siRNA干扰、RIP-Seq、LC-MS/MS等手段，研究这些LncRNA对mammospheres形成、干性维持、小鼠致瘤，癌细胞侵袭转移、药物耐受变化；寻找LncRNA通过靶基因或互作蛋白，影响下游Hippo及相关信号，调控TNBC-CSC干性维持、转移复发分子生物机制。研究结果将助于加深了解低氧对TNBC转移复发具重要理论与临床价值。

Hypoxia is a major effector to tumor malignancy and development in solid tumor microenvironment. Cancer stem cells (CSC) play a critical role on tumor metastasis, drug resistance and recurrence. Our previous studies using HIFa-knocked down triple-negative breast cancer (TNBC) showed a HIF1a-dependant hypoxic features of cell invasion, cancer stem cell enrichment, gene and LncRNA expressions. DNA sequences and bio-informatics analysis indicated that three new LncRNAs may coordinately regulate Hippo signaling to involve in CSC stemness maintenance and tumor cell invasion. Interfering one of LncRNAs led to decreased stemness of BCSC and invasive ability. Thus, it raises an intriguing scientific question that these HIF1a-dependant novel LncRNAs may play roles in stemness maintenance and cell invasion of TNBC. To further verify this hypotheses, we try to study the mechanism of these LncRNAs in regulation of mammospheres formation, stemness maintenance, drug resistance of TNBC-CSC and tumor cell invasion and metastasis in vitro and in vivo using siRNA, RIP-Seq, and LC-MS/MS to find the downstream targets, interacting proteins or related signaling associated with Hippo. The results of this program will have critical scientific and clinical values for understanding tumor metastasis and recurrence of TNBC.