Activation of hypoxia-inducible factors (HIFs) as a result of intratumoral hypoxia modulates a cascade of molecular pathways thus leading to angiogenesis and metastasis in many solid tumors, including breast cancer (BC). In our paper, we report a regulatory axis of HIF-1, SNHG1, miR-199a-3p, and mitochondrial transcription factor A (TFAM) involved in tumor angiogenesis and metastasis under hypoxic conditions in BC. The expression of SNHG1 was determined in human BC cells cultured in hypoxia (1% O₂, 24 h) and normoxia (20% O₂, 24 h). Cultured MDA-MB-231 cells were assayed for the proliferation, migration, invasion, angiogenesis in vitro by using EdU staining, transwell chamber assays, Matrigel-based angiogenesis assays, tumorigenesis, and lung metastasis in vivo by using an orthotopic-transplant model of human BC. Dual-luciferase reporter assay, chromatin immunoprecipitation quantitative polymerase chain reaction assay, fluorescence in situ hybridization assay, RNA-binding protein immunoprecipitation assay, and RNA pull-down were performed to test interaction between HIF-1 and SNHG1, SNHG1 and miR-199a-3p, miR-199a-3p and TFAM. SNHG1 was increased under hypoxic conditions at a HIF-1-dependent manner. SNHG1 knockdown tempered MDA-MB-231 cell proliferation, migration, invasion, angiogenesis, in vitro, tumorigenesis, and lung metastasis in vitro. SNHG1 was co-expressed with miR-199a-3p and regulated the TFAM, a target gene of miR-199a-3p. SNHG1 increased the TFAM by binding with miR-199a-3p, thus promoting BC development and metastasis. These results support a regulatory axis consisting of HIF-1, SNHG1, miR-199a-3p, and TFAM during BC development and metastasis under hypoxic conditions, providing an opportunity to develop targeted therapeutics for BC.

中文翻译：

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HIF-1/SNHG1/miR-199a-3p/TFAM 轴解释了乳腺癌缺氧条件下的肿瘤血管生成和转移

肿瘤内缺氧导致缺氧诱导因子 (HIF) 的激活调节一系列分子途径，从而导致许多实体瘤（包括乳腺癌 (BC)）的血管生成和转移。在我们的论文中，我们报告了 HIF-1、SNHG1、miR-199a-3p 和线粒体转录因子 A (TFAM) 的调控轴，这些轴参与了 BC 缺氧条件下的肿瘤血管生成和转移。SNHG1在低氧（1% O ₂ , 24 h）和常氧（20% O ₂, 24 小时）。体外培养的 MDA-MB-231 细胞的增殖、迁移、侵袭、血管生成通过使用 EdU 染色、transwell 室测定、基于基质胶的血管生成测定、肿瘤发生和体内肺转移通过使用原位移植模型进行测定。人类 BC。进行双荧光素酶报告基因检测、染色质免疫沉淀定量聚合酶链反应检测、荧光原位杂交检测、RNA 结合蛋白免疫沉淀检测和 RNA pull-down 以测试 HIF-1 和 SNHG1、SNHG1 和 miR-199a 之间的相互作用。 3p、miR-199a-3p 和 TFAM。SNHG1 在缺氧条件下以 HIF-1 依赖性方式增加。SNHG1 敲低缓和了 MDA-MB-231 细胞增殖、迁移、侵袭、血管生成、体外、肿瘤发生和体外肺转移。SNHG1 与 miR-199a-3p 共表达并调节 TFAM，这是 miR-199a-3p 的靶基因。SNHG1 通过与 miR-199a-3p 结合来增加 TFAM，从而促进 BC 的发展和转移。这些结果支持由 HIF-1、SNHG1、miR-199a-3p 和 TFAM 在缺氧条件下 BC 发展和转移过程中组成的调节轴，为开发 BC 靶向治疗提供了机会。