Abstract
BackgroundAccumulating studies have revealed that aberrant expression of circular RNAs (circRNAs) is widely involved in the tumorigenesis and progression of malignant cancers, including colorectal cancer (CRC). Nevertheless, the clinical significance, levels, features, biological function, and molecular mechanisms of novel circRNAs in CRC remain largely unexplored.MethodsCRC-related circRNAs were identified through bioinformatics analysis and verified in clinical specimens by qRT–PCR and in situ hybridization (ISH). Then, in vitro and in vivo experiments were performed to determine the clinical significance of, functional roles of, and clinical characteristics associated with circIL4R in CRC specimens and cells. Mechanistically, RNA pull-down, fluorescence in situ hybridization (FISH), luciferase reporter, and ubiquitination assays were performed to confirm the underlying mechanism of circIL4R.ResultsCircIL4R was upregulated in CRC cell lines and in sera and tissues from CRC patients and was positively correlated with advanced clinicopathological features and poor prognosis. Functional experiments demonstrated that circIL4R promotes CRC cell proliferation, migration, and invasion via the PI3K/AKT signaling pathway. Mechanistically, circIL4R was regulated by TFAP2C and competitively interacted with miR-761 to enhance the expression of TRIM29, thereby targeting PHLPP1 for ubiquitin-mediated degradation to activate the PI3K/AKT signaling pathway and consequently facilitate CRC progression.ConclusionsOur findings demonstrate that upregulation of circIL4R plays an oncogenic role in CRC progression and may serve as a promising diagnostic and prognostic biomarker for CRC detection and as a potential therapeutic target for CRC treatment.
Highlights
Accumulating studies have revealed that aberrant expression of circular RNAs is widely involved in the tumorigenesis and progression of malignant cancers, including colorectal cancer (CRC)
The novel circRNA hsa_circ_0038718 exhibited the most significant upregulation in HCT116, DLD1, LoVo, SW620, HT29, and SW480 CRC cells compared to FHC cells; we focused on this circRNA for further study (Fig. S1a, Fig. 1b and Fig. S3h)
To further confirm the circular form of circIL4R in CRC, convergent primers were designed to amplify the linear forms of IL4R and mRNA, while divergent primers were designed to amplify the circular forms of circIL4R. Complementary DNA (cDNA) and genomic DNA (gDNA) extracted from HCT116 and DLD1 cells were used as templates for PCR
Summary
Accumulating studies have revealed that aberrant expression of circular RNAs (circRNAs) is widely involved in the tumorigenesis and progression of malignant cancers, including colorectal cancer (CRC). Circular RNAs (circRNAs), a novel class of bifunctional RNAs that possess noncoding and limited protein-coding functions, are generated from the noncanonical backsplicing junction site of precursor mRNAs and characterized by a covalently closed single-stranded loop structure [4]. Due to their lack of a 5′ cap and 3′ polyA tail, circRNAs are resistant to exonucleases and more stable than their linear RNA counterparts [5]. CircRNAs may serve as potential biomarkers for CRC diagnosis and prognosis prediction, as well as effective therapeutic targets and vital regulators of signaling pathways [18]
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