hsa_circRNA_0006528 as a competing endogenous RNA promotes human breast cancer progression by sponging miR‐7‐5p and activating the MAPK/ERK signaling pathway

Abstract

Emerging research has indicated that circular RNAs (circRNAs), a novel class of noncoding RNAs, play a vital role in human tumorigenesis and progression. Our previous results suggested that hsa_circ_0006528 (circ_0006528), a circRNA with an unknown function, mediates adriamycin resistance in human breast cancer cells. However, the role of circ_0006528 in breast cancer progression remains unknown. Here, we investigated the probable involvement of circ_0006528 in breast cancer. We analyzed a cohort of 97 patients and found that circ_0006528 expression was significantly upregulated in human breast cancer tissues compared with that in adjacent nontumorous tissues and was significantly associated with advanced tumor-nodemetastasis (TNM) stage and poor prognosis. In addition, we found that in breast cancer cells, circ_0006528 could promote DNA synthesis and cell proliferation, invasion, and migration. Downregulating circ_0006528 induced G2 phase arrest and cell apoptosis. Further mechanistic studies revealed that circ_0006528 could sponge endogenous miR-7-5p and inhibit its activity. We also identified Raf1, which activates the MAPK/ERK signaling pathway, as a target of miR-7-5p and determined that circ_0006528 promotes breast cancer growth, invasion, and migration by promoting the expression of Raf1 and activates the MAPK/ERK pathway. Thus, this study provides the first evidence of the circ_0006528/miR-7-5p/Raf1/MEK/ERK regulatory network in the development of breast cancer and suggests that circ_0006528 is a potential therapeutic target and prognostic predictor for breast cancer.breast cancer, hsa_circ_0006528, invasion, migration, miR-7-5p, proliferation | INTRODUCTIONBreast cancer is the most prevalent cancer in women worldwide and represents a serious public health problem. One complication in the clinical management of breast cancer is the tendency of malignant cells to shed into the circulation during the early stages of tumor development, 1,2 causing the formation of metastatic foci, a phenomenon that directly contributes to approximately 90% of breast cancerrelated mortality. 3,4 The precise genetic and epigenetic mechanisms that regulate the formation and malignant progression of tumors remain unclear and require further study. Therefore, it is essential to Danfeng Gao, Xiaowei Qi, and Xiufen Zhang contributed equally to this work. |

Circular RNA hsa_circRNA_002178 silencing retards breast cancer progression via microRNA‐328‐3p‐mediated inhibition of COL1A1

“…Recent studies have highlighted promising potential of circRNAs as important modulators in human cancers 17,18. Similar with our findings, a recent study linked the high expression of hsa_ circRNA_0006528 to advanced tumour-node-metastasis stage and poor outcomes in breast cancer, while inhibition of this circRNA delayed cancer development 19. Similar with our findings, a recent study linked the high expression of hsa_ circRNA_0006528 to advanced tumour-node-metastasis stage and poor outcomes in breast cancer, while inhibition of this circRNA delayed cancer development 19.…”

“…Similar with our findings, a recent study linked the high expression of hsa_ circRNA_0006528 to advanced tumour-node-metastasis stage and poor outcomes in breast cancer, while inhibition of this circRNA delayed cancer development. 19 Analogously, up-regulation of hsa_cir-cRNA_0072995 is determined in breast cancer cells; in contrast, the silencing of hsa_circRNA_0072995 restrained aggressive malignant behaviours in breast cancer. 20 Moreover, hsa_circRNA_002178 silencing inhibited inflammation in vivo through reducing TNF-α and IL-6 levels and prevented tumour growth.…”

Retracted: Circular RNA circFNDC3B protects renal carcinoma by miR‐99a downregulation

“…For instance, a study reflected myricetin exerted its efficacy via JAK1/STAT3 and MEK/ERK in skin carcinoma (Kang, Jung, Lee, & Lee, 2011). Other studies pointed out circ0009910 enhanced carcinoma via the JAK1/STAT3 pathway (Deng et al, 2018) and circRNA0006528 enhanced breast carcinoma via the MEK/ERK pathway (Gao et al, 2019). Moreover, research pointed out miR-23a exerted efficacies in pancreatic carcinoma via JAK/STAT pathway and miR-520c exerted efficacies in fibrosarcoma via MEK/ERK signaling pathway (Liu & Wilson, 2012).…”

Circular RNA hsa_circ_0000654 promotes esophageal squamous cell carcinoma progression by regulating the miR‐149‐5p/IL‐6/STAT3 pathway

“…Studies have indicated that circRNA participates in the regulation of tumor cell progression in a variety of malignancies, including aspects such as proliferation, metastasis, apoptosis, and epithelial-mesenchymal transition. 28,29 For instance, circ_0006528 facilitates human breast cancer progression by activating the MAPK/ERK signaling pathway 30 ; circ_ 0058124 modulates the carcinogenesis and invasion of NOTCH3/GATAD2A papillary thyroid carcinoma with high expression linked to adverse pathological parameters in patients, 31 and circ-PRKCI enhances the proliferation and invasion of ESCC via upregulating AKT3 expression. 32 In this study, we demonstrated that compared with normal tissues, circ_0000654 expression in ESCC tissues was remarkably increased, and its high expression was linked to the higher T stage and lymph node metastasis of ESCC patients.…”