Circular RNAs (circRNAs) have emerged as important regulators of various cellular processes and have been implicated in cancer. Previously, we reported the discovery of several dysregulated circRNAs including circPABPC1 (polyadenylate-binding protein 1) in human hepatocellular carcinoma (HCC), although their roles in HCC development remained unclear. Here, we show that circPABPC1 is preferentially lost in tumor cells from clinical samples and inhibits both intrahepatic and distant metastases in a mouse xenograft model. This tumor-suppressive function of circPABPC1 can be attributed to its inhibition of cell adhesion and migration through down-regulating a key member of the integrin family, ITGB1 (β1 integrin). Mass spectrometry and biochemical evidence demonstrate that circPABPC1 directly links ITGB1 to the 26S proteasome for degradation in a ubiquitination-independent manner. Our data have revealed an uncanonical route for integrin turnover and a previously unidentified mode of action for circRNAs in HCC that can be harnessed for anticancer treatment.

Background/Aims: Studies on the risk factors and outcomes of peritonitis within the first 6 months in peritoneal dialysis patients are sparse. This study aims to investigate the risk factors associated with early-onset peritonitis (EOP) and its influence on patients’ technique survival and mortality. Methods: This is a retrospective observational cohort study. A total of 483 patients who had at least one episode of peritonitis were enrolled and followed from March 1, 2002, to August 31, 2016, at our center. According to the time to first peritonitis, we divided patients into two groups: EOP (≤ 6 months, n=167) and late-onset peritonitis (LOP, >6 months, n=316). Logistic regression was used to analyze the factors associated with EOP. A Cox proportional hazards model was constructed to examine the influence of EOP on clinical outcomes. Results: Of the 483 patients, 167 (34.6%) patients developed their first episode of peritonitis within the first 6 months. The EOP patient group had more male patients, a shorter time on peritoneal dialysis (PD), lower serum albumin levels at the time of PD initiation and a higher peritonitis rate (P<0.05). The EOP patient group had fewer infections with Gram-negative organisms (P=0.013) and more culture-negative peritonitis (P=0.014) than the LOP patient group for the first episode of peritonitis. The multivariate logistic regression analysis showed that factors associated with EOP included male gender (odds ratio (OR) 1.920, 95% confidence interval (CI) 1.272-2.897, P=0.002) and a low serum albumin level at the start of PD (OR 0.950, 95% CI 0.914-0.986, P=0.007). In the Cox proportional hazards model, EOP was a significant predictor of all-cause mortality (hazard ratio (HR) 2.766, 95% CI 1.561-4.900, P<0.001). There were no differences between EOP and LOP for technique failure. However, in continuous analyses, a negative correlation was observed between the time to first peritonitis and technique failure (HR 0.988, 95% CI 0.980-0.997, P=0.006). In the Spearman analysis, the time to first peritonitis was negatively correlated with the peritonitis rate (r=-0.573, P<0.001). Conclusion: Male gender and a low serum albumin level before PD were strongly associated with EOP. Additionally, EOP patients had a higher risk of poor clinical outcomes. More importantly, an early peritonitis onset was associated with a high peritonitis rate.

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BackgroundThe physiological regulatory functions of circRNAs have become a topic of intensive research in recent years. Increasing evidence supports a significant role of circRNAs during cancer initiation and progression, including hepatocellular carcinoma (HCC).Materials and MethodsA bioinformatics analysis from three independent Gene Expression Omnibus (GEO) databases was performed to profile and screen the dysregulated circRNAs in HCC. RT-qPCR was used to examine the expression level of circUBAP2 in HCC and adjacent non-tumor tissues. Then, proliferation assays (CCK8 and colony formation) and migration assays (transwell and wound healing) were performed to examine effect of circUBAP2 in vitro. Immunoprecipitation, RNA pulldown, FISH, and dual-luciferase reporter assay was conducted to explore the circUBAP2-related mechanism for regulating HCC progression. Moreover, a mouse xenograft model and a mouse lung metastasis model confirmed the effect of circUBAP2 in vivo.ResultsIn this study, we found a novel circRNA: circUBAP2, which was identified by bioinformatics analysis. Among 91 HCC patients, circUBAP2 was significantly upregulated in HCC tissues, and negatively correlated with aggressive clinical characteristics and prognosis. Functional assays demonstrated that circUBAP2 promoted cell proliferation, colony formation, migration, and invasion in vitro. Moreover, circUBAP2 enhanced tumor growth and pulmonary metastasis in vivo. Mechanistically, circUBAP2 acts as a competing endogenous RNA (ceRNA) for miR-194-3p, a tumor suppressor in HCC. We confirmed that MMP9 was direct target for miR-194-3p, which was regulated by circUBAP2.ConclusionCircUBAP2 plays a significant role in promoting HCC via the miR-194-3p/MMP9 pathway and could serve as a promising prognostic biomarker and novel therapeutic target for HCC patients.