P2.12-10 The Circular RNA cESRP1 Sensitizes Small Cell Lung Cancer to Chemotherapy

Abstract

Circular RNAs (circRNAs), a novel class of non-coding RNAs, have been drawn lots of attention in the pathogenesis of human cancers. However, the biological roles and clinical significance of Circular RNA (circRNAs) in chemosensitivity are not fully understood. In this study, we aim to investigate the biological function, mechanism and clinical significance of hsa-circ-0084927, which we termed ESRP1 gene derived circRNA (cESRP1), in small cell lung cancer (SCLC). Differentially expressed circRNAs between chemoresistant cell line and chemosensitive cell line were identified by circRNA microarray and confirmed by qRT-PCR. The functional roles of cESRP1 were demonstrated by a series of in-vitro and in-vivo experiments. The miRNA RNA pull-down, RNA immunoprecipitation, serial deletion analysis and luciferase analyses were used to investigate the potential mechanisms of cESRP1. The results showed that cESRP1 expression was significantly downregulated in chemoresistant cell lines in comparison with parental chemosensitive cell lines. cESRP1 controlled multiple drugs sensitivity through miR-93-5p in SCLC. In exploring the underlying interaction between cESRP1 and miR-93-5p, we identified that cytoplasmic cESRP1 directly binds to miR-93-5p and inhibits the transcriptional repression of miR-93-5p, thereby up-regulating miR-93-5p downstream target-Smad7/p21 expression and forming a negative feedback loop to regulates TGF-β signaling pathway-induced epithelial-mesenchymal transition. Furthermore, interfering cESRP1 expression or inhibiting TGF-β signaling pathway by inhibitors altered tumor chemotherapy response in mice xenografts including PDX model. In addition, we found cESRP1 was low expressed in SCLC tissues and associated with the patient’s survival prognosis. Together, our findings reveal the indispensable role of cESRP1 in negative regulation of Smad7/P21-dependent TGF signaling pathway involvement in EMT-induced chemotherapy resistance, providing insights toward a better understanding of the mechanism of resistance to chemotherapy drugs and peripheral recurrence of SCLC.