Abstract
ObjectiveCirc-centro-some/spindle pole-associated protein (CSPP1) has been confirmed to be characterized in diverse human malignancies and its ectopic expression may regulate tumor progression and development. However, in hepatocellular carcinoma (HCC), its biological role, clinical significance and molecular mechanism are still unclear.MethodsCirc-CSPP1 expression and its prognostic values in HCC tissues were detected by qRT-PCR or in situ hybridization (ISH), and enriched by using Rnase R. The functional experiments (Circ-CSPP1 was overexpressed or knocked down) were performed in HCC cells. The HCC cell growth was analyzed by CCK-8 assay, transwell, wound healing and colony formation assays. The interation between circ-CSPP1 and miR-577/miR-577 and cyclin E2 (CCNE2) were determined by dual luciferase assay or RNA binding protein immunoprecipitation (RIP) assay. The RNA fluorescence in situ hybridization (FISH) assay was used to detect the subcellular distribution. Finally, an in vivo nude mouse tumor model was constructed.ResultsIn HCC patients and cells, circ-CSPP1 was aberrantly expressed, and its upregulation predicted poor prognosis, and closely correlated with tumor size and TNM stage. Circ-CSPP1 resisted RnaseR digestion, indicating it is a circular RNA structure. Moreover, overexpression of circ-CSPP1 promoted HCC cell viability, colony formation, migration, and invasion in vitro. Knockdown of circ-CSPP1 showed contrary results. Circ-CSPP1 acts as a miR-577 sponge and positively regulated the target of miR-577, CCNE2. Besides, miR-577 inhibitor rescued the suppressive effects of circ-CSPP1 knockdown on HCC cell growth, whereas was completely reversed by silencing of CCNE2. Finally, the in vivo experiments confirmed that circ-CSPP1 knockdown regulated xenograft tumor volume and downregulated CCNE2, p-Rb, E2F1 and c-myc expression.ConclusionThese findings revealed that circ-CSPP1 contributed to HCC progression by positively regulating CCNE2 via miR-577, thus established its potential as new a prognostic and therapeutic marker for HCC patients.
Highlights
Hepatocellular carcinoma (HCC) ranks the fifth leading and third-most lethal cancer globally [1], with a poor prognosis result from high incidence of metastasis and Circular RNAs, represented in all types of organisms, are a naturally occurring family of noncoding RNAs formed by two mechanisms, ‘exon skipping’Sun et al Cancer Cell Int (2020) 20:202 and ‘direct back-splicing’
Circ‐CSPP1was upregulated in HCC tissues and cells To confirm the differential expression of circ-centrosome/spindle pole-associated protein 1 (CSPP1) in 72 human HCC tissues (HCC), qRT-PCR analysis was performed
Results showed that circ-CSPP1 was remarkedly higher in HCC tissues (Tumor) than that in the adjacent normal tissues (Normal) (P < 0.01, Fig. 1e)
Summary
Hepatocellular carcinoma (HCC) ranks the fifth leading and third-most lethal cancer globally [1], with a poor prognosis result from high incidence of metastasis and Circular RNAs (circRNAs), represented in all types of organisms, are a naturally occurring family of noncoding RNAs formed by two mechanisms, ‘exon skipping’Sun et al Cancer Cell Int (2020) 20:202 and ‘direct back-splicing’. CircRNAs has been widely and successfully identified due to the achievements in the bioinformatics analysis, technique of high-throughput sequencing and novel computational methods. Recently studies reported the novel roles of circRNAs in the initiation and development of cancers [7], indicating their potential as promising cancer markers. Increasing evidences have reported the novel role of circRNAs in the growth of ovarian and colorectal cancers [8], which could regulate DNA damage in breast cancer cells [9]. A circRNA (hsa_circ_0001806) derived from centrosome/spindle pole-associated protein 1 (CSPP1), has been identified to promote the progression of human B cell lymphoma [12] and human breast cancer [13]. Circ-CSPP1 promoted cell proliferation, invasion and migration [14]. Reports considering the expression profile, functional roles of circ-CSPP1 and regulatory relationship with its target miRNAs and targets, are lacking
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