circGNB1 Facilitates Triple-Negative Breast Cancer Progression by Regulating miR-141-5p-IGF1R Axis

Abstract

As an intriguing class of RNA, circular RNAs (circRNAs) are vital mediators of various diseases including cancers. However, the biological role and underlying mechanism of the majority of circRNAs are still ambiguous in the progression of triple-negative breast cancer (TNBC). In this study, we characterized and further investigated hsa_circ_0009362 (circGNB1) by reanalyzing the circRNA microarray profiling in our previous study. Validating by qRT-PCR, circGNB1 was overexpressed in TNBC cell lines and high expression of circGNB1 was associated with worse clinical features and survival outcomes. The expression of circGNB1 was positively correlated with tumor size and clinical stage, and high expression of circGNB1 was an independent risk factor for TNBC patients. Cell proliferation, colony formation, wound-healing and mouse xenograft assays were carried out to investigate the functions of circGNB1. Both in vitro and in vivo assays revealed that knockdown of circGNB1 significantly suppressed cell proliferation, migration and tumor growth. Subsequently, we performed luciferase reporter assays and RNA immunoprecipitation assays to elucidate the underlying molecular mechanism of circGNB1. The results showed that circGNB1 sponges miR-141-5p and facilitates TNBC progression by upregulating IGF1R. Altogether, our study demonstrated the pivotal role of circGNB1-miR-141-5p-IGF1R axis in TNBC growth and metastasis though the mechanism of competing endogenous RNAs. Therefore, circGNB1 may have the potential to be a therapeutic target and novel prognostic biomarker for TNBC.

Potential Diagnostic and Prognostic Utility of miR-141, miR-181b1, and miR-23b in Breast Cancer

“…The worse OS associated with miR-141 and miR-181 can be explained by their suggested oncogenic role. Conversely, our results are completely at odds with Ping et al, who demonstrated that high expression of miR-141 was associated with better OS in TNBC patients [ 67 ]. One intrinsic limitation of our study is the small sample size, which did not allow us to study the associations between the three studied miRNAs and the clinical characteristics of the patients.…”

Novel Regulators of the IGF System in Cancer

“…Interestingly, circRASSF2 regulates laryngeal squamous-cell carcinoma cells malignancy by sponging miR-302b-3p and enhancing the expression of IGF1R [ 101 ]. Similarly, circGNB1 sponges miR-141-5p and facilitates triple-negative breast cancer progression by upregulating the IGF1R [ 102 ]. A circRNA derived from backsplicing of the IGF1R itself, named circIGF1R, is detectable in hepatocellular carcinoma clinical specimens and promotes cell proliferation by activating the PI3K/Akt pathway [ 103 ].…”

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 ].…”

“…Certain circRNAs also play pivotal roles in promoting the invasion and metastasis of TNBC. 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 ].…”