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环状 RNA 0048856 通过与 ABCC1 竞争 miR-193a-5p/miR-98-5p 的结合位点促进肺癌顺铂耐药和肿瘤发生。

Circ_0048856 competes with ABCC1 for miR-193a-5p/miR-98-5p binding sites to promote the cisplatin resistance and tumorigenesis in lung cancer.

机构信息

Department of Thoracic Surgery, Leshan City People's Hospital, Leshan, China.

出版信息

J Chemother. 2023 Feb;35(1):39-52. doi: 10.1080/1120009X.2022.2043515. Epub 2022 Mar 15.

Abstract

Although cisplatin (DDP)-based therapy is the most predominant chemotherapeutic strategy used for lung cancer, drug resistance usually occurs after several cycle use of it. Circular RNAs (circRNAs) are found to be involved in the chemoresistance in lung cancer. Hence, this study aimed to clarify the role and mechanism of circ_0048856 in lung cancer tumorigenesis and DDP resistance. The levels of circ_0048856, miR-193a-5p, miR-98-5p and ABCC1 (ATP Binding Cassette Subfamily C Member 1) were determined by qRT-PCR and western blotting. In vitro assays were conducted by cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine (EDU) assay, flow cytometry and transwell assay, respectively. The binding interaction was verified using dual-luciferase reporter assay and RIP assay. experiment was performed by the establishment of murine xenograft model. Circ_0048856 was highly expressed in DDP-resistant lung cancer tissues and cells. Functionally, circ_0048856 silencing re-sensitized DDP-resistant lung cancer cells to DDP, as well as suppressed cell growth and invasion in lung cancer and . Mechanistically, circ_0048856 acted as the sponge for miR-193a-5p or miR-98-5p, which targeted ABCC1. Furthermore, rescue experiments showed that inhibition of miR-193a-5p or miR-98-5p reversed the effects of circ_0048856 knockdown on lung cancer cells. Besides that, overexpression of miR-193a-5p or miR-98-5p suppressed cell tumorigenesis and reduced DDP resistance in lung cancer, which were attenuated by ABCC1 up-regulation. Circ_0048856 knockdown suppressed tumor growth and reduced DDP resistance in lung cancer by miR-193a-5p/ABCC1 or miR-98-5p/ABCC1 axis, indicating a novel strategy for efficient application of DDP in lung cancer.

摘要

虽然基于顺铂(DDP)的治疗是肺癌最主要的化疗策略,但在几个周期的使用后通常会发生耐药性。环状 RNA(circRNA)被发现参与肺癌的化疗耐药性。因此,本研究旨在阐明 circ_0048856 在肺癌发生和 DDP 耐药中的作用和机制。通过 qRT-PCR 和 Western blot 测定 circ_0048856、miR-193a-5p、miR-98-5p 和 ABCC1(ATP 结合盒亚家族 C 成员 1)的水平。通过细胞计数试剂盒-8 测定、5-乙炔基-2'-脱氧尿苷(EDU)测定、流式细胞术和 Transwell 测定分别进行体外测定。通过双荧光素酶报告基因测定和 RIP 测定验证结合相互作用。通过建立小鼠异种移植模型进行实验。circ_0048856 在 DDP 耐药性肺癌组织和细胞中高表达。功能上,circ_0048856 沉默使 DDP 耐药性肺癌细胞对 DDP 重新敏感,并抑制肺癌细胞的生长和侵袭。在机制上,circ_0048856 作为 miR-193a-5p 或 miR-98-5p 的海绵,靶向 ABCC1。此外,挽救实验表明,抑制 miR-193a-5p 或 miR-98-5p 逆转了 circ_0048856 敲低对肺癌细胞的影响。除此之外,miR-193a-5p 或 miR-98-5p 的过表达抑制了肺癌细胞的肿瘤发生并降低了 DDP 耐药性,这被 ABCC1 的上调所减弱。circ_0048856 敲低通过 miR-193a-5p/ABCC1 或 miR-98-5p/ABCC1 轴抑制肺癌的肿瘤生长和降低 DDP 耐药性,为 DDP 在肺癌中的有效应用提供了一种新策略。

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