CircRNF10-DHX15 interaction suppressed breast cancer progression by antagonizing DHX15-NF-κB p65 positive feedback loop

Abstract

Background Breast cancer (BC) is a common threat to women. The continuous activation of nuclear factor kappa B (NF-κB) signaling pathway contributes to the development of BC. This study aimed to investigate the role of a circular RNA (circRNF10) in BC progression and regulating NF-κB signaling pathway. Methods Bioinformatics analysis, RT-qPCR, subcellular fractionation, FISH, RNase R treatment, and actinomycin D assay were used to explore the expression and characteristics of circRNF10 in BC. The biological functions of circRNF10 in BC were analyzed by MTT assay, colony formation assay, wound healing assay, and Transwell assay. RNA pulldown and RIP assay were used to identify the interaction between circRNF10 and DEAH (Asp-Glu-Ala-His) box helicase 15 (DHX15). The impact of circRNF10-DHX15 interaction on NF-κB signaling pathway was explored by western blot, IF, and co-IP. Furthermore, dual-luciferase reporter assay, ChIP, and EMSA were performed to assess the effect of NF-κB p65 on DHX15 transcription. Results CircRNF10 was downregulated in BC, and lower expression of circRNF10 was related to poor prognosis of patients with BC. CircRNF10 inhibited the proliferation and migration of BC. Mechanically, circRNF10-DHX15 interaction sequestered DHX15 from NF-κB p65, thereby inhibiting the activation of NF-κB signaling pathway. On the other hand, NF-κB p65 enhanced DHX15 transcription by binding to the promoter of DHX15. Altogether, circRNF10 impaired the DHX15-NF-κB p65 positive feedback loop and suppressed the progression of BC. Conclusion CircRNF10-DHX15 interaction suppressed the DHX15-NF-κB p65 positive feedback loop, thereby inhibiting BC progression. These findings provide new insights in the continuous activation of NF-κB signaling pathway and raised potential therapeutic approach for BC treatment.

Bacteriocins attenuate Listeria monocytogenes–induced intestinal barrier dysfunction and inflammatory response

“…P38, as a stress-related protein kinase, is an important enzyme of MAPK signaling pathway (Falcicchia et al 2020). The heterodimers formed by P65 are responsible for gene transcription when activating the canonical NF-κB signaling pathway (Zheng et al 2023), and the activation of canonical NF-κB is closely related to the inflammatory response. The research demonstrated that through downregulating the NF-κB and MAPK pathways induced by L. monocytogenes, bacteriocins may inhibit the expression of inflammatory cytokines.…”

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

“…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 ] . There are also some circRNAs whose expression levels were low in TNBC, such as CircPTK2 [ 51 ] , CircNR3C2 [ 58 ] , circFBXW7 [ 11 ] , circRNF10 [ 85 ] , and circCCDC85A [ 86 ] . Overexpressing these circRNAs greatly reduces the ability of TNBC cells to grow and vice versa.…”

“…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.…”

“…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] .…”

Versatile function of NF-ĸB in inflammation and cancer

“…Moreover, p65 enhances the transcription of DHX15 in the nucleus to increase its levels. However, circRNF10 suppresses the DHX15/p65 complex to impair its nuclear transfer and suppress the NF-κB axis [ 233 ]. Table 3 and Fig.…”