Background CircRNAs have been reported to be related to hepatocellular carcinoma (HCC) development. Limited studies have revealed the expression profile of circRNAs in tumor and paratumour normal samples in HCC patients. Methods The expression of circRNAs, mRNA and miRNA was detected by Real-time PCR. An immunofluorescence assay was performed to detect the level of 5mC and 5hmC. Dual luciferase assay was used to confirm the interaction between miRNA and circRNA. CCK8, wound healing and transwell assays were used to check the viability, migration and invasion of HCC cells. Migration and invasion assays was used to confirm the metastasis in vivo. Results We found that circASPH was significantly increased in HCC tumor samples and that the level of circASPH was closely related to the overall survival (OS) of HCC patients. Mechanistically, circASPH could regulate the methylation of promoter and gene expression of Hydrocyanic Oxidase 2 (HAO2) to promote HCC progression by acting as a sponge for miR-370, which targeted the DNMT3b and increased the 5mC level. Conclusions Our study determined that circASPH could promote the methylation and expression of HAO2 and could be considered an important epigenetic regulator in HCC progression.
Background Colorectal cancer (CRC) is the fourth most common cancer in men and the third most common cancer in women worldwide. The incidence and mortality of CRC was increasing rapidly in China. Lymph node-negative colorectal cancer patients with synchronous liver metastasis (LNLM1) was defined as “skip” lymph vascular invasion on hepatic metastasis, who presenting poor prognosis. We aiming to investigate the potential mechanism for the “skip” lymph vascular invasion on hepatic metastasis in colorectal cancer. Methods The microarray was applied for screening the transcription landscape of circRNA in lymph node negative CRC patients with synchronous liver metastasis (LNLM1) or without liver metastasis (LNLM0). The gain- and loss-of-function experiments was conducted in CRC cell lines and animal models. The RNA pull-down, RNA immunoprecipitation n was further employed in exploring the detailed mechanism of circRNA and associated target genes. Results We identified the aberrant increased circRNA circ_0124554 (also entitled as circ-LNLM) in tumor tissues of LNLM1 patients comparing with either the tumor tissues of LNLM0 or adjacent tissues of LNLM1. Circ-LNLM1 expression was highly corrected with liver metastasis and vascular invasion. Ectopic expression of cytoplasmic located circ-LNLM could promote invasion of CRC cells and induced the liver metastasis in animal models through the direct binding with AKT. The phosphorylation of AKT (T308/S473) was activated due to the blocked ubiquitination site of Lys in 0-52aa peptide of circ-LNLM. Endogenous plasma expression of circ-LNLM induced poor prognosis of LNLM1 and could distinguish LNLM1 patients from LNLM0. Conclusions The circ-LNLM blocked the ubiquitination of AKT could promote the early metastasis especially for the lymph node-negative colorectal cancer patients with synchronous liver metastasis. The circ-LNLM might be prognosis and diagnosis biomarker for LNLM1 patients.
BackgroundEmerging studies have investigated circRNAs as significant regulation factors in multiple cancer progression. Nevertheless, the biological functions and underlying mechanisms of circRNAs in colorectal cancer progression remain unclear.MethodsA novel circRNA (circ-GALNT16) was identified by microarray and qRT-PCR. A series of phenotype experiments in vitro and vivo were performed to investigate the role of circ-GALNT16 in CRC. FISH, RNA pulldown assay, RIP assay, RNA sequencing, coimmunoprecipitation, and ChIP were constructed to explore the molecular mechanisms of circ-GALNT16 in colorectal cancer.ResultsCirc-GALNT16 was downregulated in colorectal cancer and negatively correlated with poor prognosis. Circ-GALNT16 suppressed the proliferation and metastasis ability of colorectal cancer in vitro and vivo. Mechanistically, circ-GALNT16 could bind to the KH3 domain of heterogeneous nuclear ribonucleoprotein K (hnRNPK), which resulted in the SUMOylation of hnRNPK. Additionally, circ-GALNT16 could enhance the hnRNPK-p53 complex by facilitating the SUMOylation of hnRNPK. Furthermore, RNA sequencing assay identified serpin family E member 1 as the target gene of circ-GALNT16 at the transcriptional level. Rescue assays revealed that circ-GALNT16 regulated the expression of Serpine1 by inhibiting the deSUMOylation of hnRNPK mediated by SUMO specific peptidase 2 and then regulating the sequence-specific DNA binding ability of the hnRNPK-p53 transcriptional complex.ConclusionsCirc-GALNT16 suppressed CRC progression via inhibiting Serpine1 expression through adjusting the sequence-specific DNA binding ability of the SENP2-mediated hnRNPK-p53 transcriptional complex and might work as a biomarker and therapeutic target for CRC.
Ubiquitin-conjugating enzyme E2 J1 (UBE2J1) has been proved to participate in the ubiquitination of multiple substrate proteins. However, the underlying mechanisms of UBE2J1 as a ubiquitin-conjugating enzyme participating in cancer development and progression remain largely unknown. Here, we identified that UBE2J1 was downregulated in colorectal cancer (CRC) tissues and cell lines which were mediated by DNA hypermethylation of its promoter, and decreased UBE2J1 was associated with poor prognosis. Functionally, UBE2J1 serving as a suppressor gene inhibited proliferation and metastasis of CRC cells. Mechanistically, UBE2J1-TRIM25, forming an E2-E3 complex, physically interacted and targeted RPS3 for ubiquitination and degradation at the K214 residue. The downregulated RPS3 caused by UBE2J1 overexpression restrained NF-κB translocation into the nucleus and therefore inactivates the NF-κB signaling pathway. Our study revealed a novel role of UBE2J1 mediated RPS3 poly-ubiquitination and degradation in disrupting the NF-κB signaling pathway, which may serve as a novel and promising biomarker and therapeutic target for CRC.
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