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, Matrigelbased 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.

Antrodia camphorata and coenzyme Q0, a novel quinone derivative of Antrodia camphorata, impede HIF‐1α and epithelial‐mesenchymal transition/metastasis in human glioblastoma cells

“…The dysregulation and overexpression of HIF‐1α by hypoxia have been heavily implicated in cancer biology, specifically in tumor migration/invasion 42 . In contrast, in control cells, AC treatment silenced HIF‐1α translation in a dose‐dependent manner (Figure 3A).…”

Noncoding RNAs as regulators of STAT3 pathway in gastrointestinal cancers: Roles in cancer progression and therapeutic response

“…245,246 The activation of HIF-1α occurs in the hypoxic condition that enhances tumor progression and can mediate changes in the expression level of miRNAs. 247 HIF-1α reduced the expression of miR-34a in p53-defective colorectal tumor cells which increased the proliferation and migratory abilities of tumor cells by activating STAT3. However, when the expression of p53 was high, it counteracted the impact of HIF-1α and enhanced the expression of miR-34a which in turn miR-34a suppressed STAT3 signaling via PPP1R11 downregulation and impaired colorectal tumor progression.…”

“…Hypoxia is well‐known to promote metastasis and advancement of disease 245,246 . The activation of HIF‐1α occurs in the hypoxic condition that enhances tumor progression and can mediate changes in the expression level of miRNAs 247 . HIF‐1α reduced the expression of miR‐34a in p53‐defective colorectal tumor cells which increased the proliferation and migratory abilities of tumor cells by activating STAT3.…”

miR-125 in Breast Cancer Etiopathogenesis: An Emerging Role as a Biomarker in Differential Diagnosis, Regenerative Medicine, and the Challenges of Personalized Medicine

“…Overexpression of miR-199a-3p targets the c-Met and mTOR pathways, increases doxorubicin sensitivity and causes G1 phase arrest, thus reducing cell invasion and promoting doxorubicin-induced apoptosis [ 87 ]. This miR also confers resistance to cisplatin treatment by downregulating TFAM [ 88 ] and, at the same time, promotes BC development and metastasis under hypoxic conditions by controlling the regulatory axis consisting of HIF-1, SNHG1, and TFAM [ 89 ]. The same study mentioned above [ 87 ] also shows that in TNBC patients, additional circulating miR (i.e., miR-19a/b-3p, miR-25-3p, miR-22-3p, miR-210-3p and miR-93-5p) are deregulated as well and control several molecular pathways involved in drug resistance, making them amenable to be used as BC biomarkers, together with let-7a-5p, miR-100-5p and miR-101-3p, identified in another study [ 90 ].…”