Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
Gut Liver. 2023 May 15;17(3):389-403. doi: 10.5009/gnl210195. Epub 2022 Aug 17.
BACKGROUND/AIMS: Chemoresistance is a common event after cancer chemotherapy, which is associated with the deregulation of circular RNAs (circRNAs). The objective of this study was to clarify the role of circ-LDLRAD3 in cisplatin (DDP)-resistant gastric cancer (GC).
The expression of circ-LDLRAD3, miR-588, and SRY-box transcription factor 5 (SOX5) mRNA was detected by quantitative real-time polymerase chain reaction. Cell viability and the half maximal inhibitory concentration (IC) value were measured by CCK8 assay. Cell proliferation was assessed by colony formation and EdU assays. Cell apoptosis and cell invasion were assessed by flow cytometry assay and transwell assay, respectively. The expression of SOX5 protein was detected by Western blotting. A xenograft model was established to verify the role of circ-LDLRAD3 . Exosomes were isolated by differential centrifugation and identified by transmission electron microscopy and the expression of exosome-related proteins.
circ-LDLRAD3 was overexpressed in DDP-resistant GC tissues and cells. circ-LDLRAD3 knockdown decreased the IC of DDP-resistant cells and suppressed cell proliferation, survival and invasion. miR-588 was a target of circ-LDLRAD3, and miR-588 inhibition attenuated the inhibition of DDP resistance, proliferation, survival and invasion in DDP-resistant GC cells caused by circ-LDLRAD3 knockdown. SOX5 was a target of miR-588, and the inhibition of the DDP resistance, proliferation, survival and invasion of DDP-resistant GC cells by miR-588 restoration was largely rescued SOX5 overexpression. circ-LDLRAD3 knockdown inhibited DDP resistance and tumor growth . circ-LDLRAD3 was overexpressed in exosomes isolated from DDP-resistant GC cells.
circ-LDLRAD3 knockdown reduced DDP resistance and blocked the malignant development of DDP-resistant GC by modulating the miR-588/SOX5 pathway.
背景/目的：化疗耐药是癌症化疗后常见的事件，与环状 RNA（circRNA）的失调有关。本研究旨在阐明 circ-LDLRAD3 在顺铂（DDP）耐药胃癌（GC）中的作用。
通过实时定量聚合酶链反应检测 circ-LDLRAD3、miR-588 和性别决定区 Y 框转录因子 5（SOX5）mRNA 的表达。通过 CCK8 测定法测量细胞活力和半最大抑制浓度（IC）值。通过集落形成和 EdU 测定评估细胞增殖。通过流式细胞术测定和 Transwell 测定分别评估细胞凋亡和细胞侵袭。通过 Western blot 检测 SOX5 蛋白的表达。建立异种移植模型验证 circ-LDLRAD3 的作用。通过差速离心分离外泌体，并通过透射电子显微镜和外泌体相关蛋白的表达鉴定。
circ-LDLRAD3 在 DDP 耐药 GC 组织和细胞中过表达。circ-LDLRAD3 敲低降低了 DDP 耐药细胞的 IC，并抑制了细胞增殖、存活和侵袭。miR-588 是 circ-LDLRAD3 的靶标，miR-588 抑制可减弱 circ-LDLRAD3 敲低引起的 DDP 耐药、增殖、存活和侵袭的抑制作用在 DDP 耐药 GC 细胞中。SOX5 是 miR-588 的靶标，miR-588 恢复对 DDP 耐药 GC 细胞的 DDP 耐药、增殖、存活和侵袭的抑制作用，很大程度上被 SOX5 过表达所挽救。circ-LDLRAD3 敲低抑制 DDP 耐药和肿瘤生长。circ-LDLRAD3 在 DDP 耐药 GC 细胞分离的外泌体中过表达。
circ-LDLRAD3 敲低通过调节 miR-588/SOX5 通路降低 DDP 耐药性并阻断 DDP 耐药 GC 的恶性发展。
