Abstract
BackgroundCircular 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.MethodsBioinformatic 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.ResultsCircDIDO1 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.ConclusionsCircDIDO1 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.
Highlights
Circular RNAs play important roles in cancer development and progression
CircDIDO1 is downregulated in gastric cancer (GC) and its low level predicts poor prognosis To identify new circRNAs in GC, we extracted circRNA microarray data (GSE83521 and GSE89143) from Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/) to analyze circRNA expression profiles [16, 17]
PCR results showed that circDIDO1 could be amplified by divergent primers from cDNA but not gDNA of GC cells while the linear transcript could be amplified by convergent primers from both (Fig. 1c)
Summary
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. Circular RNAs (circRNAs), a group of transcripts characterized by covalently closed structure, are generated from exons or introns of their parental genes [3]. The function of circRNAs is not fully understood, recent studies have shown that circRNAs participate in many physiological and pathological processes by regulating epigenetic modification, gene transcription, alternative splicing, RNA stability, and protein translation [4]. CircRNAs are found stably present in the circulation of cancer patients, making them candidate biomarkers for cancer diagnosis
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