EIF4A3-mediated circ_0042881 activates the RAS pathway via miR-217/SOS1 axis to facilitate breast cancer progression

Abstract

Breast cancer (BC) is one of the most frequent cancer-related deaths in women worldwide. Studies have shown the potential impact of circRNAs in multiple human tumorigeneses. Research on the vital signaling pathways and therapeutic targets of circRNAs is indispensable. Here, we aimed to investigate the clinical implications and underlying mechanisms of circ_0042881 in BC. RT-qPCR validated circ_0042881 was notably elevated in BC tissues and plasma, and closely associated with BC clinicopathological features. Functionally, circ_0042881 significantly accelerated the proliferation, migration, and invasion of BC cells in vitro and tumor growth and metastasis in vivo. Mechanistically, circ_0042881 promoted BC progression by sponging miR-217 to relieve its inhibition effect in son of sevenless 1 (SOS1), which further activated RAS protein and initiated downstream signaling cascades, including MEK/ERK pathway and PI3K/AKT pathway. We also demonstrated that treatment of BAY-293, an inhibitor of SOS1 and RAS interaction, attenuated BC progression induced by circ_0042881 overexpression. Furthermore, Eukaryotic initiation factor 4A-III (EIF4A3) could facilitate circ_0042881 circularization. Altogether, we proposed a novel signaling network in which circ_0042881, induced by EIF4A3, influences the process of BC tumorigenesis and metastasis by miR-217/SOS1 axis.

Circular RNAs in Breast Cancer: An Update

“…A CCK-8 assay substantiated that cell proliferation was significantly attenuated after circ_0042881 depletion, whereas circ_0042881 overexpression accelerated cell viability [57]. EdU and colony formation experiments further revealed that depletion of circ_0042881 hindered the proliferation of MDA-MB-231 and MCF-7 cells, whereas circ_0042881 overexpression provoked the phenotypes [57]. A subsequent Transwell assay illustrated that circ_0042881 depletion led to a decrease in the quantity of migrant and invasive cells, while overexpressing circ_0042881 reversed this effect [57].…”

“…Circ_0042881, induced by EIF4A3, exhibited increased expression in BC tissues and plasma, and showed strong correlation with clinicopathological features [57]. A CCK-8 assay substantiated that cell proliferation was significantly attenuated after circ_0042881 depletion, whereas circ_0042881 overexpression accelerated cell viability [57]. EdU and colony formation experiments further revealed that depletion of circ_0042881 hindered the proliferation of MDA-MB-231 and MCF-7 cells, whereas circ_0042881 overexpression provoked the phenotypes [57].…”

“…Interestingly, KLF5 drived the transcription of FUS, which could enhance the back-splicing of circEZH2, forming a novel FUS/circEZH2/KLF5 feedback loop [56]. Circ_0042881, induced by EIF4A3, exhibited increased expression in BC tissues and plasma, and showed strong correlation with clinicopathological features [57]. A CCK-8 assay substantiated that cell proliferation was significantly attenuated after circ_0042881 depletion, whereas circ_0042881 overexpression accelerated cell viability [57].…”

The therapeutic potential of circular RNA in triple-negative breast cancer

“…Many circRNAs are highly expressed in TNBC, such as circRRM2 [ 80 ] , circ0000851 [ 81 ] , circEZH2 [ 82 ] , circ0042881 [ 83 ] , and circZFAND6 [ 84 ] [ Table 1 ]. A majority of them can enhance the miRNA sponge function, thus promoting the proliferation, migration, and invasion ability of TNBC, including circ0000851/miR-1183 [ 48 ] , circEZH2/miR-217-5p [ 82 ] , circ0042881/miR-217 [ 83 ] , and circZFAND6/miR-647 [ 84 ] , thereby increasing tumor growth. In addition, a small portion of them can play a role in promoting tumor growth by encoding or binding proteins, including circCAPG/CAPG-171aa [ 76 ] , circEIF6/EIF6-224aa [ 77 ] , circKIF4A/EIF4A3 [ 70 ] , CircSNX25/COPB1 [ 71 ] , and circEIF3H/IGF2BP2 [ 73 ] .…”

“…The common metastases of TNBC include brain, liver, lung, and bone metastasis, which ultimately leads to a high mortality rate due to the presence of lesion metastasis in different parts and degrees. Many circRNAs are highly expressed in TNBC, such as circRRM2 [80] , circ0000851 [81] , circEZH2 [82] , circ0042881 [83] , and circZFAND6 [84] [Table 1]. A majority of them can enhance the miRNA sponge function, thus promoting the proliferation, migration, and invasion ability of TNBC, including circ0000851/ miR-1183 [48] , circEZH2/miR-217-5p [82] , circ0042881/miR-217 [83] , and circZFAND6/miR-647 [84] , thereby increasing tumor growth.…”