Abstract
BackgroudAccumulating evidences indicate that circular RNAs (circRNAs), a class of non-coding RNAs, play important roles in tumorigenesis. However, the function of circRNAs in triple negative breast cancer (TNBC) is largely unknown.MethodsWe performed circRNA microarrays to identify circRNAs that are aberrantly expressed in TNBC cell lines. Expression levels of a significantly upregulated circRNA, circGFRA1, was detected by quantitative real-time PCR (qRT-PCR) in TNBC cell lines and tissues. Kaplan-Meier survival analysis was used to explore the significance of circGFRA1 in clinical prognosis. Then, we examined the functions of circGFRA1 in TNBC by cell proliferation, apoptosis and mouse xenograft assay. In addition, luciferase assay was used to explore the miRNA sponge function of circGFRA1 in TNBC.ResultsMicroarray analysis and qRT-PCR verified a circRNA termed circGFRA1 that was upregulated in TNBC. Kaplan-Meier survival analysis showed that upregulated circGFRA1 was correlated with poorer survival. Knockdown of circGFRA1 inhibited proliferation and promoted apoptosis in TNBC. Via luciferase reporter assays, circGFRA1 and GFRA1 was observed to directly bind to miR-34a. Subsequent experiments showed that circGFRA1 and GFRA1 regulated the expression of each other by sponging miR-34a.ConclusionsTaken together, we conclude that circGFRA1 may function as a competing endogenous RNA (ceRNA) to regulate GFRA1 expression through sponging miR-34a to exert regulatory functions in TNBC. circGFRA1 may be a diagnostic biomarker and potential target for TNBC therapy.
Highlights
Breast cancer is the most commonly diagnosed cancer in women worldwide
We conclude that circGFRA1 may act as a competing endogenous RNA (ceRNA) to regulate GFRA1 expression by decoying miR-34a, indicating that circGFRA1 can be used as a diagnostic biomarker and potential target in triple negative breast cancer (TNBC) therapy
We found that co-transfection of the mutated luciferase reporter and miR-34a mimics or miR-34a LNA had no significant effect on luciferase activity (Fig. 4d). quantitative real-time PCR (qRT-PCR) analysis further confirmed that miR-34a mimics could inhibit the expression of circGFRA1 while miR-34a LNA increased circGFRA1 expression (Fig. 4e)
Summary
It is estimated that there will be 255,180 new cases and 41,070 deaths of breast cancer in the United States in 2017 [1]. The last few decades have witnessed outstanding advances in breast cancer treatment. The prognosis for triple negative breast cancer (TNBC) remains poor. There are currently few reports describing the role of circRNAs in breast cancer. Liang G et al reported that circDENND4C is a HIF1αassociated circRNA promoting the proliferation of breast cancer under hypoxia [3]. Lu L et al provided a profile of circRNAs in breast cancer and adjacent normal-appearing tissues [4]. The function of circRNAs in TNBC progression is unclear. Revealing the role of circRNAs will be critical for understanding TNBC pathogenesis and
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