Circular RNA (circRNA) is a special type of endogenous non-coding RNA that plays an important role in carcinogenesis. However, its biological relevance in hepatocellular carcinoma (HCC) is still largely uncharacterized. Here, we aimed to explore the function and clinical implication of circ-FOXP1 in HCC. We found that circ-FOXP1 was significantly upregulated in HCC tissues, serum and cell lines., which was attributed to the upregulation of oncogenic transcription factor SOX9. Depletion of circ-FOXP1 significantly inhibited HCC cell proliferation, invasion and induced apoptosis. Nevertheless, overexpression of circ-FOXP1 displayed the opposite trend. Further mechanismic study revealed that circ-FOXP1 was preferentially located in the cytoplasm and could concurrently sponge miR-875-3p and miR-421, resulting in increasing levels of a cohort of their target oncogenes, including SOX9. Moreover, knockdown of circ-FOXP1 evidently retarded tumor growth in vivo, but this effect was significantly abolished after silencing of miR-875-3p or miR-421. Clinically, high circ-FOXP1 was closely correlated with larger tumor size, microvascular invasion, advanced TNM stage, and predicted poor prognosis. In addition, serum circ-FOXP1 level could effectively discriminate HCC patients from healthy controls. Collectively, our data clearly suggest that circ-FOXP1 is a novel driver for the tumorigenesis and aggressive progression of HCC, which provides a potential therapeutic target for patients with HCC.

Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, especially in East Asia. Even with the progress in therapy, 5-year survival rates remain unsatisfied. Chronic infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV) has been epidemiologically associated with HCC and is the major etiology in the East Asian population. The detailed mechanism, especially the changes of DNA methylation and gene expression between the two types of virus-related HCC, and their contributions to the HCC development, metastasis, and recurrence remain largely unknown. Methods: In this integrated analysis, we characterized genome-scale profiles of HBV and HCV infected HCC by comparing their gene expression pattern, methylation profiles, and copy number variations from the publicly accessible data of The Cancer Genome Atlas Program (TCGA). Results: The HLA-A, STAT1, and OAS2 genes were highly enriched and up-regulated discovered in the HCV-infected HCC. Hypomethylation but not copy number variations might be the major factor for the up-regulation of these immune-related genes in HCV-infected HCC. Conclusions: The results indicated the different epigenetic changes of HBV/HCV related hepatocarcinogenesis. The top up-regulated genes in HCV group were significantly clustered in the immune-related and defense response pathways. These findings will help us to understand the pathogenesis of HBV/HCV associated hepatocellular carcinoma.

HBV (hepatitis B virus) infection still threatens human health. Therefore, it is essential to find new effective anti-HBV compounds. Here, we identified matrine as a novel inhibitor of PKC (protein kinase C) phosphorylated kinase by screening a natural compound library. After HepG2.215 cells were treated with matrine, we carried out a phosphorylated proteomics sequence study and analyzed the prediction of related kinase expression level. In the case of HBV infection, it was found that PKC kinase mediates the activation of mitogen-activated protein kinase (MAPK) signaling pathway known as son of sevenless (SOS) activation. It was also found that PKC kinase inhibits the expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) by inhibiting the activity of activating transcription factor 2/ cAMP response element binding protein (ATF2/CREB), and this effect is independent of its activated MAPK signaling pathway. Finally, Western blot was used to detect the expression of MAPK, ATF2, CREB3 phosphorylation and nonphosphorylation in matrine-treated cells and PKC-treated cells. PKC phosphorylated kinase inhibitor-matrine suppresses the replication of HBV via modulating the MAPK/ATF2 signal. Matrine is a good clinical drug to enhance the autoimmunity in the adjuvant treatment of chronic HBV infection. Graphical Abstract

Background: 5-Fluorouracil (5-Fu) has been applied to treat pancreatic cancer, which is one of the most common types of digestive system tumors. Evidence has shown that miR-486-5p could promote the proliferation of pancreatic cancer cells. Therefore, this study aimed to investigate whether downregulation of miR-486-5p could enhance the anti-tumor effect of 5-Fu on pancreatic cancer cells. Methods: Cell Counting Kit 8 assay, flow cytometry and wound healing assays were used to detect proliferation, apoptosis and migration in PANC-1 cells. The expressions of Bcl-2, Bax, cleaved caspase 3, PTEN, p-Akt and p-ERK in PANC-1 cells were detected with Western blot assay. Results: In this study, the inhibitory effects of 5-Fu on the proliferation, migration and invasion of PANC-1 cells were significantly enhanced following transfection with miR-486-5p antagonist. In addition, downregulation of miR-486-5p markedly enhanced the pro-apoptosis effect of 5-Fu on PANC-1 cells. Moreover, bioinformatics analysis and luciferase reporter assay identified that PTEN was the directly binding target of miR-486-5p. Meanwhile, downregulation of miR-486-5p markedly enhanced the anti-tumor effect of 5-Fu in PANC-1 cells via upregulation of the level of PTEN, and downregulation of the expressions of p-ERK and p-Akt. In vivo experiments confirmed that knockdown of miR-486-5p could enhance the anti-tumor effect of 5-Fu in PANC-1 xenograft model. Conclusion: We found that the downregulation of miR-486-5p could enhance the anti-tumor effect of 5-Fu on pancreatic cancer cells. Therefore, miR-486-5p antagonist plus 5-Fu might be considered as a potential therapeutic strategy for the treatment of pancreatic cancer.

Background. Hepatocellular carcinoma (HCC) is the sixth most common kind of cancer worldwide and the third leading cause of cancer mortality. Although a few studies have shown that hydroxyacid oxidase 2 (HAO2) may prevent HCC development, the molecular mechanism is unclear. Methods. We examined the levels of HAO2 expression in 23 pairs of HCC/paracancerous tissues by quantitative real-time polymerase chain reaction (qRT-PCR) and evaluated HAO2s expression in The Cancer Genome Atlas (TCGA) database. Furthermore, we examined the biological activity of HAO2 utilizing cell-based functional assays. Additionally, we evaluated the relationship between miR-615-5p and HAO2 in Hep3B cells using a dual-luciferase reporter system and assessed the downstream regulatory mechanisms of miR-615-5p on HAO2. Finally, the nude mice tumor formation experiment was used to determine the impact of HAO2 on the tumorigenicity of HCC cells. Results. HAO2 expression was considerably underexpression in HCC tissues and cells, and patients with low HAO2 expression had poorer disease-free survival. Inhibition of cell proliferation, migration, and invasion was observed when HAO2 was overexpressed. miR-615-5p had a negative relation with HAO2, and miR-615-5p restored HAO2s biological activity in HCC cells. Additionally, the tumor volume and weight were considerably reduced in the OV-HAO2 group compared to the OV-NC group. Conclusion. HAO2 was found to be underexpressed in HCC tissues and cells, and HAO2 overexpression inhibited HCC cell motility, which was negatively regulated by miR-615-5p. Exogenous expression of HAO2 reduced the tumorigenicity of HCC cells in vivo in nude mice.