Author:
Zhang Yu,Jiang Jiajia,Zhang Jiayin,Shen Han,Wang Maoye,Guo Zhen,Zang Xueyan,Shi Hui,Gao Jiayan,Cai Hui,Fang Xinjian,Qian Hui,Xu Wenrong,Zhang Xu
Abstract
Abstract
Background
Circular RNAs (circRNAs) play important roles in cancer development and progression. The purpose of this study is to identify aberrantly expressed circRNAs in gastric cancer (GC), unravel their roles in GC progression, and provide new targets for GC diagnosis and therapy.
Methods
Bioinformatic analyses were performed to identify the aberrantly expression of hsa_circ_0061137 (termed as circDIDO1) in GC. Gain- and loss-of-function studies were performed to examine the biological roles of circDIDO1 in GC progression. Tagged RNA affinity purification, mass spectrometry, immunofluorescence, co-immunoprecipitation, and Western blot were used to identify circRNA-interacting and circRNA-encoded proteins. RNA sequencing, qRT-PCR, and Western blot were performed to analyze circRNA-regulated downstream target genes and signaling pathways. Mouse tumor models were used to analyze the effects of circDIDO1 on GC growth and metastasis.
Results
CircDIDO1 was transcribed from human DIDO1 (death-inducer obliterator 1) gene and formed by back-splicing of exons 2–6 of the linear transcript. circDIDO1 was down-regulated in GC tissues and its low levels were associated with larger tumor size, distal metastasis, and poor prognosis. CircDIDO1 overexpression inhibited while knockdown promoted GC cell proliferation, migration and invasion. CircDIDO1 overexpression suppressed GC growth and metastasis in mouse tumor models. Mechanistically, circDIDO1 encoded a novel 529aa protein that directly interacted with poly ADP-ribose polymerase 1 (PARP1) and inhibited its activity. CircDIDO1 also specifically bound to peroxiredoxin 2 (PRDX2) and promoted RBX1-mediated ubiquitination and degradation of PRDX2, which led to the inactivation of its downstream signaling pathways.
Conclusions
CircDIDO1 is a new circRNA that has tumor suppressor function in GC and it may serve as a potential prognostic biomarker and therapeutic target for GC.
Funder
National Natural Science Foundation of China
Distinguished Young Scholar Project of Jiangsu Natural Science Foundation
Key Research and Development Program of Jiangsu Province
Technology Development Project of Zhangjiagang Aoyang Hospital
Major Natural Science Reasearch Project for Universities in Jiangsu Province
Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province
six talent peaks project in jiangsu province
Priority Academic Program Development of Jiangsu Higher Education Institutions
Research Innovation Project for Graduate Students in Jiangsu Province
Clinical Major Disease Project of Suzhou Health Commission
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Molecular Medicine
Cited by
68 articles.
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