Shi Huijuan, Li Hui, Zhen Tiantian, Dong Yu, Pei Xiaojuan, Zhang Xiangliang
Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, P.R. China.
Department of Pathology, Shenzhen Hospital of Southern Medical University, Shenzhen 518110, P.R. China.
Mol Ther Nucleic Acids. 2020 Jun 5;20:252-264. doi: 10.1016/j.omtn.2019.12.028. Epub 2020 Jan 10.
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive pancreatic cancer with poor survival rate. Circular RNAs (circRNAs) signatures have been identified in some human cancers, but there are little data concerning their presence in PDAC. We investigated the role of hsa_circ_001653, a newly identified circRNA, in the development of PDAC. hsa-circ-001653 expression was measured in 83 paired normal and tumor tissues surgically resected from PDAC patients. Phenotypic changes of PDAC cells were evaluated by assays for cell viability, cell cycle, invasion, and apoptosis. Tube-like structure formation of human umbilical vein endothelial cells (HUVECs) was examined in the presence of PDAC cells. Cross-talk between hsa_circ_001653 and microRNA-377 (miR-377)/human homeobox C6 (HOXC6) was assessed using dual-luciferase reporter assay, Ago2 immunoprecipitation, and northern blot analysis. Nude mice were inoculated with human PDAC cells for in vivo analysis. hsa_circ_001653 was an upregulated circRNA in PDAC. Silencing of hsa_circ_001653 in PDAC cells via RNA interference inhibited cell viability, cell-cycle progression, in vitro angiogenesis, and invasive properties, showing a pro-apoptotic effect. hsa_circ_001653 was found to bind to miR-377, which in turn repressed HOXC6 expression. Inhibition of miR-377 by its specific inhibitor restored cell viability, cell-cycle progression, in vitro angiogenesis, and invasive properties in PDAC cells lacking endogenous hsa_circ_001653. When nude mice were inoculated with human PDAC cells, inhibition of hsa_circ_001653 had a therapeutic effect. Collectively, the present study provides an enhanced understanding of hsa_circ_001653 as a therapeutic target for PDAC.
胰腺导管腺癌（PDAC）是一种极具侵袭性的胰腺癌，生存率很低。环状RNA（circRNA）特征已在一些人类癌症中得到鉴定，但关于其在PDAC中的存在情况的数据很少。我们研究了一种新鉴定的circRNA——hsa_circ_001653在PDAC发生发展中的作用。在83对从PDAC患者手术切除的正常组织和肿瘤组织中检测了hsa-circ-001653的表达。通过细胞活力、细胞周期、侵袭和凋亡检测评估PDAC细胞的表型变化。在存在PDAC细胞的情况下检测人脐静脉内皮细胞（HUVEC）的管状结构形成。使用双荧光素酶报告基因检测、Ago2免疫沉淀和Northern印迹分析评估hsa_circ_001653与微小RNA-377（miR-377）/人类同源盒C6（HOXC6）之间的相互作用。将人PDAC细胞接种到裸鼠体内进行体内分析。hsa_circ_001653是PDAC中上调的circRNA。通过RNA干扰沉默PDAC细胞中的hsa_circ_001653可抑制细胞活力、细胞周期进程、体外血管生成和侵袭特性，显示出促凋亡作用。发现hsa_circ_001653与miR-377结合，进而抑制HOXC6的表达。用其特异性抑制剂抑制miR-377可恢复缺乏内源性hsa_circ_001653的PDAC细胞的细胞活力、细胞周期进程、体外血管生成和侵袭特性。当将人PDAC细胞接种到裸鼠体内时，抑制hsa_circ_001653具有治疗效果。总的来说，本研究增进了对hsa_circ_001653作为PDAC治疗靶点的理解。
