Mutual regulation of HIF-1α and circ-UBE2G1 under hypoxic microenvironment promotes thyroid cancer metastasis

To investigate the mechanism by which hypoxia-inducible factor (HIF)-1α and circ-UBE2G1 mutually regulate and promote thyroid cancer (THCA) metastasis under hypoxic microenvironment.

The GEPIA database was used to analyze the expression characteristics and correlation between circ-UBE2G1 and HIF-1α in THCA. The relationship of circ-UBE2G1 and miR-330-3p with survival rate was analyzed using Kaplan-Meier survival curve. After THCA cells were exposed to hypoxia, HIF-1α was silenced by transfection to analyze its regulation for circ-UBE2G1 transcription. The targeting relationship between miR-330-3p and either circ-UBE2G1 or HIF-1α was verified by sequence prediction and dual luciferase reporter assay. The effects of HIF-1α overexpression and circ-UBE2G1 silencing on THCA cell migration and invasion were analyzed after corresponding transfections. A tumor-bearing nude mouse model was established by subcutaneous injection of THCA cells with HIF-1α overexpression and circ-UBE2G1 silencing, respectively. THCA tissues and adjacent normal samples were clinically collected to analyze the expression levels and correlations of circ-UBE2G1, miR-330-3p, and HIF-1α.

Bioinformatics analysis showed that circ-UBE2G1 was positively correlated with HIF-1α (P<0.01), and its high expression was associated with a low survival rate in THCA patients (P=0.024). Inhibition of HIF-1α blocked the promotive effect of hypoxia on circ-UBE2G1 (P<0.05). Silencing circ-UBE2G1 inhibited the migration and invasion of THCA cells (P<0. 05), and reversed the promotive effect of HIF-1α on these processes (P<0. 05). Dual luciferase reporter gene assay revealed that miR-330-3p targeted both circUBE2G1 and HIF-1α (P<0.05). Silencing circ-UBE2G1 led to increased levels of miR-330-3p (P<0.05), whereas increasing miR-330-3p inhibited the expression of HIF-1α (P<0.05). In clinical THCA samples, both circ-UBE2G1 and HIF-1α were increased and positively correlated (P<0.05), while miR-330-3p was lowly expressed and negatively correlated with both circ-UBE2G1 and HIF-1α (P<0.05).

Hypoxia promotes the transcription of circ-UBE2G1 by inducing HIF-1α expression, and circ-UBE2G1 promotes HIF-1α expression by targeting miR-330-3p, thereby promoting THCA metastasis.