Circular RNA CDR1as Mediated by Human Antigen R (HuR) Promotes Gastric Cancer Growth via miR-299-3p/TGIF1 Axis

Author:

Li Rong12,Xu Xuejing1,Gao Shuo1,Wang Junyi3,Hou Jie2,Xie Zhenfan2,Luo Lan2,Shen Han12,Xu Wenrong2,Jiang Jiajia24

Affiliation:

1. Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing University, 321 Zhongshan Road, Nanjing 210008, China

2. Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang 212013, China

3. Centre of Clinical Laboratory, The First Affiliated Hospital of Soochow University, 899 Pinghai Road, Suzhou 215006, China

4. Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, 279 Jingang Road, Suzhou 215600, China

Abstract

Background: Gastric cancer (GC) remains a common malignancy worldwide with a limited understanding of the disease mechanisms. A novel circular RNA CDR1as has been recently reported to be a crucial regulator of human cancer. However, its biological role and mechanism in the GC growth are still far from clear. Methods: Small interfering RNAs (siRNAs), lentivirus or plasmid vectors were applied for gene manipulation. The CDR1as effects on the GC growth were evaluated in CCK8 and colony formation assays, a flow cytometry analysis and mouse xenograft tumor models. A bioinformatics analysis combined with RNA immunoprecipitation (RIP), RNA pull-down assays, dual-luciferase reporter gene assays, Western blot, reverse transcription–quantitative polymerase chain reaction (RT-qPCR) and functional rescue experiments were used to identify the CDR1as target miRNA, the downstream target gene and its interaction with human antigen R (HuR). Results: The CDR1as overexpression promoted the GC growth in vitro and in vivo and reduced the apoptotic rate of GC cells. Its knockdown inhibited the GC cell proliferation and viability and increased the cell apoptotic rate. Proliferation-related proteins PCNA and Cyclin D1 and apoptosis-related proteins Bax, Bcl-2, Caspase-3 and Caspase-9 were regulated. Mechanically, the cytoplasmic CDR1as acted as a miR-299-3p sponge to relieve its suppressive effects on the GC cell growth. Oncogenic TGIF1 was a miR-299-3p downstream target gene that mediated the promotive effects of CDR1as and regulated the PCNA and Bax levels. HuR interacted with CDR1as via the RRM2 domain and positively regulated the CDR1as level and its oncogenic role as well as downstream target TGIF1. Conclusions: CDR1as promotes the GC growth through the HuR/CDR1as/miR-299-3p/TGIF1 axis and could be used as a new therapeutic target for GC.

Funder

Key Research and Development Program of Jiangsu Province

Technology Project of Zhangjiagang

Innovation Fundation for Medicine and Education Synergy of Jiangsu University

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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