J Cancer 2021; 12(1):207-216. doi:10.7150/jca.48896

Research Paper

Berberine inhibits the Warburg effect through TET3/miR-145/HK2 pathways in ovarian cancer cells

Jie Li1✉, Yuliang Zou2, Meili Pei2, Yun Zhang1, Yu Jiang2

1. Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
2. Department of Gynecology and Obstetrics, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

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Citation:
Li J, Zou Y, Pei M, Zhang Y, Jiang Y. Berberine inhibits the Warburg effect through TET3/miR-145/HK2 pathways in ovarian cancer cells. J Cancer 2021; 12(1):207-216. doi:10.7150/jca.48896. Available from https://www.jcancer.org/v12p0207.htm

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Abstract

Background: Berberine, as an alkaloid, has a significant antitumor effect, but its mechanism in tumor metabolism, especially the Warburg effect has not been elucidated.

Objectives: To study the molecular mechanism of berberine regulating the Warburg effect in ovarian cancer cells.

Methods: Treatment by berberine in SKOV3 and 3AO cells or inhibited by miR-145 inhibitor transfection in berberine-treated cells to examine the changes in HK2 expression, glucose consumption and lactate production. The methylation status in the promoter region of pre-miR-145 gene was examined by bisulfite sequencing. Dual-luciferase reporter assay was conducted to verify the direct binding of miR-145 to HK2. Finally, the expression of TET3 in ovarian cancer was investigated by quantitative real-time PCR and immunohistochemistry.

Results: We found berberine inhibited the Warburg effect by up-regulating miR-145, miR-145 targeted HK2 directly. Berberine increased the expression of miR-145 by promoting the expression of TET3 and reducing the methylation level of the promoter region of miR-145 precursor gene. We further found that TET3 expression was negatively correlated with clinical stage and pathological grade.

Conclusions: Our results revealed berberine increased the TET3-mediated demethylation and promoted the suppression of miR-145 on HK2 to antagonize the Warburg effect of ovarian cancer cells.

Keywords: Berberine, the Warburg effect, methylation, ovarian cancer, miR-145