The HIF‐1/SNHG1/miR‐199a‐3p/TFAM axis explains tumor angiogenesis and metastasis under hypoxic conditions in breast cancer

Abstract 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% O 2 , 24 h) and normoxia (20% O 2 , 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.