The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer

Abstract

Background: Increasing studies have shown that circRNA is closely related to the carcinogenesis and development of many cancers. However, biological functions and the underlying molecular mechanism of circRNAs in triplenegative breast cancer (TNBC) remain largely unclear so far. Methods: Here, we investigated the expression pattern of circRNAs in four pairs of TNBC tissues and paracancerous normal tissues using RNA-sequencing. The expression and prognostic significance of circSEPT9 were evaluated with qRT-PCR and in situ hybridization in two TNBC cohorts. The survival curves were drawn by the Kaplan-Meier method, and statistical significance was estimated with the log-rank test. A series of in vitro and in vivo functional experiments were executed to investigate the role of circSEPT9 in the carcinogenesis and development of TNBC. Mechanistically, we explored the potential regulatory effects of E2F1 and EIF4A3 on biogenesis of circSEPT9 with chromatin immunoprecipitation (ChIP), luciferase reporter and RNA immunoprecipitation (RIP) assays. Furthermore, fluorescent in situ hybridization (FISH), luciferase reporter and biotin-coupled RNA pull-down assays were implemented to verify the relationship between the circSEPT9 and miR-637 in TNBC. Results: Increased expression of circSEPT9 was found in TNBC tissues, which was positively correlated with advanced clinical stage and poor prognosis. Knockdown of circSEPT9 significantly suppressed the proliferation, migration and invasion of TNBC cells, induced apoptosis and autophagy in TNBC cells as well as inhibited tumor growth and metastasis in vivo. Whereas up-regulation of circSEPT9 exerted opposite effects. Further mechanism research demonstrated that circSEPT9 could regulate the expression of Leukemia Inhibitory Factor (LIF) via sponging miR-637 and activate LIF/Stat3 signaling pathway involved in progression of TNBC. More importantly, we discovered that E2F1 and EIF4A3 might promote the biogenesis of circSEPT9. Conclusions: Our data reveal that the circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer through circSEPT9/miR-637/LIF axis. Therefore, circSEPT9 could be used as a potential prognostic marker and therapeutical target for TNBC.

Construction of circRNA-based ceRNA Network to Reveal the Role of circRNAs in the Progression and Prognosis of Hepatocellular Carcinoma

“…Previous studies have shown that circRNA has transcriptional disorder in many cancers, including HCC, which might be related to tumor proliferation and metastasis. Zheng et al found that by inhibiting the expression of circSEPT9, the proliferation, migration and invasion of triple-negative breast cancer (TNBC) could be inhibited, and the apoptosis and autophagy of TNBC cells could be induced [18]. The result showed that circRNA played signi cant role in occurrence and development of refractory breast cancer.…”

The Roles of ceRNAs-Mediated Autophagy in Cancer Chemoresistance and Metastasis

“…The roles of ncRNAs such as lncRNAs [ 133 , 134 ], circRNAs [ 73 , 135 ], and miRNAs [ 133 , 136 ] have been recognized in cancer metastasis and autophagy. Figure 3 summarizes the potential roles of ceRNA-mediated autophagy in modulating metastasis.…”

Clinical value and potential mechanisms of COL8A1 upregulation in breast cancer: a comprehensive analysis

“…Moreover, breast cancer gene 1 (BRCA1) and P53 mutations, EGFR upregulation, and cytokeratin 19 downregulation have been associated with TNBC [19,20]. It has also been reported that circSEPT9 promotes tumor formation and TNBC progression [21]. Recently, ∆Np63 has been found to participate in breast cancer metastasis and dissemination [22].…”