Abstract
BackgroundHypoxia is a key feature of breast cancer, which affects cancer development, metastasis and metabolism. Previous studies suggested that circular RNAs (circRNAs) could participate in cancer progression and hypoxia regulation. This study aimed to investigate the role of circRNA differentially expressed in normal cells and neoplasia domain containing 4C (circDENND4C) in breast cancer progression under hypoxia.MethodsForty-three patients with breast cancer were involved in this study. Breast cancer cell lines MDA-MB-453 and SK-BR-3 were cultured under hypoxia (1% O2) for experiments in vitro. The expression levels of circDENND4C, microRNA-200b (miR-200b) and miR-200c were measured by quantitative real-time polymerase chain reaction. Glycolysis was investigated by glucose consumption, lactate production and hexokinase II (HK2) protein level. Migration and invasion were evaluated via trans-well assay and protein levels of matrix metallopeptidase 9 (MMP9) and MMP2. The interaction between circDENND4C and miR-200b or miR-200c was explored by bioinformatics analysis, luciferase assay and RNA immunoprecipitation. Murine xenograft model was established to investigate the anti-cancer role of circDENND4C in vivo.ResultscircDENND4C highly expressed in breast cancer was up-regulated in response to hypoxia. Knockdown of circDENND4C decreased glycolysis, migration and invasion in breast cancer cells under hypoxia. circDENND4C was validated as a sponge of miR-200b and miR-200c. Deficiency of miR-200b or miR-200c reversed the suppressive effect of circDENND4C knockdown on breast cancer progression. Moreover, silence of circDENND4C reduced xenograft tumor growth by increasing miR-200b and miR-200c.ConclusioncircDENND4C silence suppresses glycolysis, migration and invasion in breast cancer cells under hypoxia by increasing miR-200b and miR-200c.
Highlights
Hypoxia is a key feature of breast cancer, which affects cancer development, metastasis and metabolism
The expression of circDENND4C is increased in breast cancer cells under hypoxia To explore the role of circDENND4C
By dividing into two groups according to the mean value of circDENND4C level, the high expression of circDENND4C was associated with tumor node metastasis stage, lymph node metastasis and tumor size (P < 0.05) but not with age, menopause and subtype (P > 0.05) (Table 1)
Summary
Hypoxia is a key feature of breast cancer, which affects cancer development, metastasis and metabolism. Previous studies suggested that circular RNAs (circRNAs) could participate in cancer progression and hypoxia regulation. This study aimed to investigate the role of circRNA differentially expressed in normal cells and neoplasia domain containing 4C (circDENND4C) in breast cancer progression under hypoxia. Xu et al reported that circRNA transcriptional adaptor 2A (circTADA2A) inhibits cell proliferation, migration and invasion by regulating microRNA-203a-3p/suppressor of cytokine signaling 3 (SOCS3) axis in breast cancer [7]. Zhang et al suggested that circRNA has_ circ_0052112, generated from zinc finger 83, could promote cell migration and invasion by sponging microRNA-125a-5p in breast cancer [8]. Previous study indicated that high expression of circDENND4C promotes cell proliferation in breast cancer under hypoxia condition [10]. The role and mechanism of circDENND4C in breast cancer progression remain largely unknown
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