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Abstract
BackgroundChemoresistance is one of the major obstacles for cancer therapy in the clinic. Circular RNAs (circRNAs) are involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC) and chemoresistance. This study aimed to explore the role and molecular mechanism of circ_0006168 in Taxol resistance of ESCC.MethodsThe expression levels of circ_0006168, microRNA-194-5p (miR-194-5p) and jumonji domain containing 1C (JMJD1C) were measured by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. The half-inhibition concentration (IC50) value of Taxol was evaluated by Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was evaluated by CCK-8 and colony formation assays. Cell migration and invasion were detected by transwell assay. Cell apoptosis was determined by flow cytometry. The interaction between miR-194-5p and circ_0006168 or JMJD1C was predicted by bioinformatics analysis (Circinteractome and TargetScan) and verified by dual-luciferase reporter and RNA Immunoprecipitation (RIP) and RNA pull-down assays. The mice xenograft model was established to investigate the roles of circ_0006168 in vivo.ResultsCirc_0006168 and JMJD1C were upregulated and miR-194-5p was downregulated in ESCC tissues, ESCC cells, and Taxol-resistant cells. Functionally, knockdown of circ_0006168 or JMJD1C increased Taxol sensitivity of ESCC in vitro via inhibiting cell proliferation, migration and invasion, and promoting apoptosis. Moreover, circ_0006168 could directly bind to miR-194-5p and JMJD1C was verified as a direct target of miR-194-5p. Mechanically, circ_0006168 was a sponge of miR-194-5p to regulate JMJD1C expression in ESCC cells. Furthermore, JMJD1C overexpression reversed the promotive effect of circ_0006168 knockdown on Taxol sensitivity. Besides, circ_0006168 silence suppressed tumor growth in vivo.ConclusionCirc_0006168 facilitated Taxol resistance in ESCC by regulating miR-194-5p/JMJD1C axis, providing a promising therapeutic target for ESCC chemotherapy.
Highlights
Esophageal cancer (EC) is a common malignant tumor worldwide, ranking the 7th in incidence and 6th in mortality [1, 2]
Base on the analysis of bioinformatics software (Circinteractome and TargetScan), we found that circ_0006168 and Jumonji domain containing 1C (JMJD1C) had complementary binding sequence for miR-194-5p, which stimulated us to assume the competing endogenous RNAs (ceRNAs) regulatory network of circ_0006168/ miR-194-5p/JMJD1C in Taxol resistance of esophageal squamous cell carcinoma (ESCC)
Our study found that circ_0006168 expression in ESCC tissues was obviously higher than that in adjacent normal tissues (Fig. 1A)
Summary
Esophageal cancer (EC) is a common malignant tumor worldwide, ranking the 7th in incidence (approximately 572,000 new cases) and 6th in mortality (approximately 509,000 deaths) [1, 2]. Esophageal squamous cell carcinoma (ESCC) is the most common histological type in. It is essential to explore the mechanism of chemotherapy resistance or sensitivity for improving the prognosis of ESCC. CircRNA circ-TTC17 acted as a tumor suppressor through repressing ESCC cell growth and migration [12]. CircRNA hsa_ circ_0000337 served as a tumor promoter in ESCC via promoting cell proliferation, migration and invasion [13]. Hsa_circ_0002483 inhibited the progression and enhanced the Taxol sensitivity of non-small cell lung cancer via regulating miR-182-5p [18]. Circular RNAs (circRNAs) are involved in the pathogenesis of esophageal squamous cell carcinoma (ESCC) and chemoresistance. This study aimed to explore the role and molecular mechanism of circ_0006168 in Taxol resistance of ESCC
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