Department of Hepatopancreatobillary Surgery, Xuzhou Cancer Hospital, Xuzhou, China.
Department of Oncology, Xuzhou Cancer Hospital, Xuzhou, China.
Exp Physiol. 2020 Dec;105(12):2141-2153. doi: 10.1113/EP088399. Epub 2020 Nov 13.
What is the central question of this study? Does hsa_circ_001653 influence the development of gastric cancer (GC) and if so how? What is the main finding and its importance? Bioinformatics analysis revealed the presence of differentially expressed hsa_circ_001653 in GC and adjacent normal tissues, and this was strongly related to the pathology of patients with GC. Knockdown of hsa_circ_001653 suppressed the proliferation, invasion and migration of GC cells, while inducing cell apoptosis via miR-377-mediated NR6A1 inhibition. The effect of hsa_circ_001653 and miR-377 on tumour growth in GC was further confirmed in vivo.
Gastric cancer (GC) is one of the leading causes of human mortality through malignant tumours. Circular RNAs (circRNAs) have been identified as binding to microRNAs (miRNAs) to modulate the progression of tumours. This study explores the role of hsa_circ_001653, a newly identified circRNA, in the development of GC. hsa_circ_001653 expression was measured in 86 paired normal and tumour tissues surgically resected from GC patients. Cross-talk between hsa_circ_001653 and microRNA-377 (miR-377)/nuclear receptor subfamily 6, group A, member 1 (NR6A1) was assessed using bioinformatics analysis, dual-luciferase reporter assay, Ago2 immunoprecipitation and western blot analysis. A series of functional experiments were carried out to elucidate the role of hsa_circ_001653 in GC cell proliferation, invasion, migration and apoptosis, and its underlying molecular mechanisms. Nude mice were inoculated with GC cells for in vivo analysis. hsa_circ_001653 was found to be an up-regulated circRNA in GC tissues and cells. Down-regulation of hsa_circ_001653 inhibited GC cell proliferation, migration and invasion, while stimulating cell apoptosis. hsa_circ_001653 was found to bind to miR-377, which targeted NR6A1 and repressed its expression. Inhibition of miR-377 and overexpression of NR6A1 restored the proliferation, migration and invasion in GC cells lacking hsa_circ_001653. Furthermore, inhibition of hsa_circ_001653 attenuated tumour growth in nude mice inoculated with GC cells. Collectively, the demonstration that hsa_circ_001653 exerts its anticancer effects by regulating the miR-377-NR6A1 axis increases our understanding of gastric cancer pathophysiology. The findings uncover new potential therapeutic targets for GC.
本研究的核心问题是什么？hsa_circ_001653 是否影响胃癌（GC）的发展，如果是，如何影响？主要发现及其重要性是什么？生物信息学分析显示 hsa_circ_001653 在 GC 和相邻正常组织中的表达存在差异，这与 GC 患者的病理密切相关。hsa_circ_001653 的敲低抑制了 GC 细胞的增殖、侵袭和迁移，同时通过 miR-377 介导的 NR6A1 抑制诱导细胞凋亡。体内实验进一步证实了 hsa_circ_001653 和 miR-377 对 GC 肿瘤生长的影响。
胃癌（GC）是人类因恶性肿瘤导致死亡的主要原因之一。环状 RNA（circRNAs）已被鉴定为与 microRNAs（miRNAs）结合，从而调节肿瘤的进展。本研究探讨了一种新鉴定的 circRNA hsa_circ_001653 在 GC 发展中的作用。测量了 86 对 GC 患者手术切除的正常和肿瘤组织中的 hsa_circ_001653 表达。使用生物信息学分析、双荧光素酶报告基因检测、AGO2 免疫沉淀和 Western blot 分析评估 hsa_circ_001653 与 microRNA-377（miR-377）/核受体亚家族 6，A 组，成员 1（NR6A1）之间的相互作用。进行了一系列功能实验，以阐明 hsa_circ_001653 在 GC 细胞增殖、侵袭、迁移和凋亡中的作用及其潜在的分子机制。用 GC 细胞接种裸鼠进行体内分析。发现 hsa_circ_001653 在 GC 组织和细胞中呈上调表达。hsa_circ_001653 的下调抑制 GC 细胞增殖、迁移和侵袭，同时刺激细胞凋亡。发现 hsa_circ_001653 与 miR-377 结合，miR-377 靶向 NR6A1 并抑制其表达。抑制 miR-377 和过表达 NR6A1 恢复了缺乏 hsa_circ_001653 的 GC 细胞的增殖、迁移和侵袭。此外，抑制 hsa_circ_001653 减弱了接种 GC 细胞的裸鼠的肿瘤生长。总之，hsa_circ_001653 通过调节 miR-377-NR6A1 轴发挥抗癌作用的证明增加了我们对胃癌病理生理学的理解。研究结果揭示了 GC 的新的潜在治疗靶点。
