CircGNB1 Facilitates Triple-Negative Breast Cancer Progression by Regulating miR-141-5p-IGF1R Axis.

Peng Liu,Yanan Kong,Xing Li,Yutian Zou,Weidong Wei,Jie Zhang,Feng Ye,Anli Yang

doi:10.3389/fgene.2020.00193

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.

Highlights

According to the global estimated cancer statistic, breast cancer is the most common malignancy and second major cause of cancer-related deaths among women worldwide (Bray et al, 2018)
By browsing the circBase database and University of California, Santa Cruz (UCSC) Genome Browser, we found that hsa_circ_0009362 is generated from exons 2 and 3 of GNB1 with no intron which is located on chromosome 1p36.33
Kaplan-Meier survival analysis showed that high expression level of circGNB1 was associated with a poor overall survival (OS) and disease-free survival (DFS) outcomes (Figures 1B,C)

Summary

INTRODUCTION

According to the global estimated cancer statistic, breast cancer is the most common malignancy and second major cause of cancer-related deaths among women worldwide (Bray et al, 2018). Regarded as a high heterogeneous disease, breast cancer can be divided into four major different molecular subtypes (Harbeck and Gnant, 2017). Among these four subtypes, triple-negative breast cancer (TNBC) is characterized by the loss of expression of human epidermal growth factor. CircKIF4A, circRAD18 and circPLK1 were identified and proved to be oncogenic regulators in the progression of breast cancer by interacting with miRNAs (Kong et al, 2019; Tang et al, 2019; Zou et al, 2019b). Our study demonstrated the pivotal role of circGNB1miR-141-5p-IGF1R axis in TNBC growth and metastasis though the mechanism of competing endogenous RNAs. circGNB1 may have the potential to be a therapeutic target and novel prognostic biomarker for TNBC

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT