Abstract
Gastric cancer (GC) is the fifth most commonly diagnosed malignancy. Paclitaxel (PTX) is an effective first-line chemotherapy drug in GC treatment, but the resistance of PTX attenuates the therapeutic effect. Circular RNA circ-PVT1 can exert the oncogenic effect in GC. But the function of circ-PVT1 involved in PTX resistance of GC is still unknown. In the present study, the expression levels of circ-PVT1, miR-124-3p and ZEB1 in PTX-resistant GC tissues and cells were detected by quantitative real-time polymerase chain reaction (RT-qPCR). PTX resistance in PTX-resistant cells was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The protein levels of Zinc finger E-box binding homeobox 1 (ZEB1), P-glycoprotein (P-gp) and glutathione S-transferase (GST-π) were detected by Western blot assay. Cell apoptosis and invasion were measured in PTX-resistant cells by flow cytometry and transwell invasion assays, severally. The interaction between miR-124-3p and circ-PVT1 or ZEB1 was predicted by starBase software, and then verified by the dual-luciferase reporter assay. The role of circ-PVT1 in PTX resistance of GC in vivo was measured by xenograft tumor model. Our results showed that circ-PVT1 expression was up-regulated in PTX-resistant GC tissues and cells. Circ-PVT1 down-regulation enhanced PTX sensitivity in PTX-resistant GC cells by negatively regulating miR-124-3p. ZEB1 served as a direct target of miR-124-3p. Circ-PVT1 enhanced ZEB1 expression by sponging miR-124-3p. Circ-PVT1 knockdown increased PTX sensitivity of GC in vivo. Taken together, our studies disclosed that circ-PVT1 facilitated PTX resistance by up-regulating ZEB1 mediated via miR-124-3p, suggesting an underlying therapeutic strategy for GC.
Highlights
Gastric cancer (GC) is the third leading cause of cancer-related death and the fifth most commonly diagnosed malignancy, accounting for 1 in 12 deaths cases in the world in 2018 [1]
We confirmed that circ-PVT1 was highly expressed in GC cell lines (MKN-45, HGC-27, MGC-803, and AGS) relative to normal human gastric epithelial cell line GES-1, in MGC-803 and AGS cells (Figure 1B)
These results suggested that circ-PVT1 might be associated with PTX resistance in GC cells
Summary
Gastric cancer (GC) is the third leading cause of cancer-related death and the fifth most commonly diagnosed malignancy, accounting for 1 in 12 deaths cases in the world in 2018 [1]. The development of surgical techniques and treatment has substantially improved, the prognosis of GC patients in China is still unfavorable [2]. Paclitaxel (PTX, known as taxol) is identified as an effective first-line chemotherapy drug in GC treatment, but the therapeutic effect of PTX gradually become worse, on account of the chemoresistance caused by diverse factors [3,4]. It is imperative to identify the molecular mechanisms of drug resistance in GC to develop the novel molecular target for improving PTX sensitivity. Circular RNAs (termed circRNAs), a class of special non-coding transcripts, have been reported as essential regulators in various biological processes of eukaryotes [5,6].
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