CircUBE2D2 (hsa_circ_0005728) promotes cell proliferation, metastasis and chemoresistance in triple-negative breast cancer by regulating miR-512-3p/CDCA3 axis

Dongwei Dou; Xiaoyang Ren; Mingli Han; Xiaodong Xu; Xin Ge; Yuanting Gu; Xinxing Wang; Song Zhao

doi:10.1186/s12935-020-01547-7

CircUBE2D2 (hsa_circ_0005728) promotes cell proliferation, metastasis and chemoresistance in triple-negative breast cancer by regulating miR-512-3p/CDCA3 axis

Cancer Cell Int. 2020 Sep 14:20:454. doi: 10.1186/s12935-020-01547-7. eCollection 2020.

Authors

Dongwei Dou¹, Xiaoyang Ren², Mingli Han¹, Xiaodong Xu¹, Xin Ge¹, Yuanting Gu¹, Xinxing Wang¹, Song Zhao³

Affiliations

¹ Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi District, Zhengzhou, 450052 China.
² Department of Information, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 China.
³ Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi District, Zhengzhou, 450052 China.

Abstract

Background: Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with a bad prognosis. Chemotherapy is still the standard of care for TNBC treatment. Circular RNAs (CircRNAs) have been recently discovered to be closely involved in the initiation and development of human cancers. Herein, we focus our attention on the functions and underlying mechanisms of circUBE2D2 in TNBC progression and chemoresistance.

Methods: The expression of circUBE2D2, miR-512-3p, and cell division cycle associated 3 (CDCA3) mRNA were determined by qRT-PCR. CCK-8, colony formation, transwell and flow cytometry assays were performed to detect cell proliferation, migration, invasion and apoptosis. Western blot assay was utilized to measure the protein level of CDCA3. RNA pull-down, luciferase reporter and RIP experiments were employed to examine the possible regulatory mechanism of circUBE2D2.

Results: CircUBE2D2 expression was elevated in TNBC tissues and cells. TNBC patients with high circUBE2D2 expression are inclined to present advanced TNM stage, lymph node metastasis and adverse prognosis. Knockdown of circUBE2D2 repressed cell proliferation, migration and invasion in vitro, and impeded tumor growth in vivo. Moreover, silencing of circUBE2D2 reduced doxorubicin resistance of TNBC cells. In-depth mechanism analysis revealed that circUBE2D2 served as a miRNA sponge to protect CDCA3 from the attack of miR-512-3p. Additionally, the tumor-suppressive effect induced by circUBE2D2 depletion was greatly impaired upon miR512-3p down-regulation or CDCA3 overexpression. Also, depletion of circUBE2D2 decreased the resistance to doxorubicin through regulating miR-512-3p/CDCA3 axis.

Conclusion: CircUBE2D2 promoted TNBC progression and doxorubicin resistance through acting as a sponge of miR-512-3p to up-regulate CDCA3 expression. Targeting circUBE2D2 combine with doxorubicin might be exploited as a novel therapy for TNBC.

Keywords: CDCA3; Triple-negative breast cancer; circUBE2D2; miR-512-3p.