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

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.

CDCA3 Is a Novel Prognostic Biomarker Associated with Immune Infiltration in Hepatocellular Carcinoma

“…Many studies have elucidated the role of CDCA3 expression in diverse tumors; for instance, CDCA3 inhibits the formation of tumors by affecting cell growth and inducing apoptosis in pancreatic cancer [ 32 ]. CDCA3 expression affects other cancers as well, such as renal cell carcinoma [ 33 ], breast cancer [ 34 ], acute myeloid leukemia [ 35 ], and non-small-cell lung cancer [ 5 ]. Recently, some studies have suggested that CDCA3 is expressed differently between normal tissues and tumor tissues; however, only few studies have explained the underlying mechanism and pathways of CDCA3 expression in HCC.…”

Regulatory mechanisms, functions, and clinical significance of CircRNAs in triple-negative breast cancer

“…Likewise, circKIF4A and circITCH were proved to upregulate its parental genes via acting as sponges for miRNAs thereby mediating TNBC progress [ 51 , 52 ]. Additionally, more miRNA-sponge functions of circRNAs have been and are being validated in TNBC, including circUBAP2/miR-661/MTA1 [ 53 ], circPLK1/miR-296-5p/PLK1 [ 54 ], circTFCP2L1/miR-7/PAK1 [ 55 ], circAHNAK1/miR-421/RASA1 [ 56 ], circAGFG1/miR-195-5p/CCNE1 [ 57 ], circZEB1/miR-448/eEF2K [ 58 ], circGNB1/miR-141-5p/IGF1R [ 59 ], circRPPH1/miR-556-5p/YAP1 [ 60 ], circCDYL/miR-190a-3p/TP53INP1 [ 61 ], circEIF3M/miR-33a/cyclinD1 [ 62 ], circUBE2D2/miR-512-3p/CDCA3 [ 63 ], and circPGAP3/miR-330-3p/Myc [ 64 ].…”

“…Majority circRNAs identified in TNBC are characterized by oncogenic features. Specifically, circRPPH1 , circSEPT9 , circGNB1 , circPGAP3 , circUBE2D2 , circRAD18 , circAGFG1 , circKIF4A , circPLK1 , circUBAP2 , circEPSTI1 , and circGFRA1 were upregulated in both TNBC cells and tissues, and high expression of these circRNAs was able to promote tumor cell proliferation both in vitro and in vivo, and was associated with larger tumor sizes and shorter survival times for TNBC patients [ 29 , 46 , 49 , 51 , 53 , 54 , 57 , 59 , 60 , 63 , 64 , 78 ]. Similarly, circZEB1 , circEIF3M , circHER2 , hsa_circ_0131242 , hsa_circ_0005320 , hsa_circ_069718 , hsa_circ_0058514 , and circTFCP2L1 were overexpressed in TNBC cells and tissues, and they appeared to promote cell proliferation and tumor growth of TNBC [ 55 , 58 , 62 , 75 , 79 – 82 ].…”

“…High expression of circSEPT9 , circGNB1 , circAGFG1 , circPGAP3 , circKIF4A , circPLK1 , circANKS1B , circUBAP2 , and ciRS-7 significantly contributed to the invasion and metastasis of TNBC cells both in vitro and in vivo, and were correlated with advanced TNM stage and poor prognosis of TNBC patients [ 45 , 47 , 49 , 51 , 53 , 54 , 57 , 59 , 64 ]. Likewise, circRPPH1 , hsa_circ_0131242 , circEIF3M , circHER2 , circUBE2D2 , circRAD18 , hsa_circ_069718 , hsa_circ_0058514 , and circTFCP2L1 also significantly promoted the migration and invasion capability of TNBC cells in vitro [ 55 , 60 , 62 , 63 , 75 , 78 , 79 , 81 , 82 ]. Conversely, the expression of circFBXW7, circAHNAK1, circTADA2A-E6, and circITCH appeared to be downregulated in TNBCs and was associated with advanced TNM stage and poor survival for TNBC patients [ 48 , 52 , 56 , 74 ].…”

“…DOX-based chemotherapy is the most frequently used treatment for TNBC [ 88 ]. Hsa_circ_0006528 , circKDM4C , circUBE2D2 , and circLARP4 were found to be associated with DOX resistance in TNBC [ 63 , 87 , 89 , 90 ]. Specifically, hsa_circ_0006528 was significantly upregulated in DOX-resistant MDA-MB-231 (MDA-MB-231/DOX) cells [ 87 ], mechanically by participating in the circ_0006528/miR-7-5p/Raf1 axis that confers chemotherapeutic resistance in TNBC [ 91 ].…”