The microRNA miR-19a is closely related to tumor formation and development and is a key oncogene. Previous studies have demonstrated that miR-19a is upregulated in multiple cancer types, including colorectal cancer (CRC). However, most of these experiments were performed in vitro, and consequently, the mechanisms underlying the effects of miR-19a on CRC are still unclear. Therefore, in the present study, we investigated the role of miR-19a in the development of solid CRC tumors. We generated KRAS 3'UTR-Mut by deleting the predicted binding site for miR-19a in KRAS, and observed that the expression of a reporter gene containing the KRAS 3'UTR in HCT116 cells was suppressed by miR-19a, while that of a reporter gene with mutant KRAS 3'UTR was unaffected by miR-19a. We observed that high miR-19a levels reduced KRAS expression. In the tube formation assay, overexpression of miR-19a exhibited anti-angiogenesis effects, which were rescued by KRAS expression. We established a nude mouse xenograft model to investigate the specific role of miR-19a in solid tumors. The results revealed that the sizes of xenograft tumors and density of blood vessels developed from HCT116 cells expressing miR-19a were smaller/lower compared with those of the control. KRAS and VEGFA levels were also reduced. In conclusion, our results revealed that miR-19a overexpression supressed KRAS expression and angiogenesis in CRC, indicating possibilities of using miR-19a in future therapeutic applications.
BackgroundThe importance of transcription factors (TFs) and epigenetic modifications in the control of gene expression is widely accepted. However, causal relationships between changes in TF binding, histone modifications, and gene expression during the response to extracellular stimuli are not well understood. Here, we analyze the ordering of these events on a genome-wide scale in dendritic cells in response to lipopolysaccharide (LPS) stimulation.ResultsUsing a ChIP-seq time series dataset, we find that the LPS-induced accumulation of different histone modifications follows clearly distinct patterns. Increases in H3K4me3 appear to coincide with transcriptional activation. In contrast, H3K9K14ac accumulates early after stimulation, and H3K36me3 at later time points. Integrative analysis with TF binding data reveals potential links between TF activation and dynamics in histone modifications. Especially, LPS-induced increases in H3K9K14ac and H3K4me3 are associated with binding by STAT1/2 and were severely impaired in Stat1−/− cells.ConclusionsWhile the timing of short-term changes of some histone modifications coincides with changes in transcriptional activity, this is not the case for others. In the latter case, dynamics in modifications more likely reflect strict regulation by stimulus-induced TFs and their interactions with chromatin modifiers.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1524-z) contains supplementary material, which is available to authorized users.
Tumor necrosis factor-α inducible protein-8 (TIPE2), initially recognized as a negative immune regulator, exerts an important role in suppressing the progression of numerous cancers. In our previous investigation, we found that TIPE2 expression displayed a decrease or absence in gastric tumor tissue, and the overexpression of TIPE2 suppressed the growth of gastric cancer tumors and cells, demonstrating that TIPE2 could be a potential medicinal target for gastric cancer treatment. However, it’s seldomly reported that several medicinal agents or candidates targeted TIPE2 for treating diseases, including gastric cancer. To identify the candidate targeting TIPE2 to fight against gastric cancer, several extractions from traditional natural medicinal plants with anti-tumor functions were employed to screen the active compounds according to bioassay-guided isolation. Interestingly, gracillin, a component from the ethyl acetate extraction of Rhizoma Paridis, was identified to induce the expression of TIPE2 and inhibit the cell proliferation in gastric cancer BGC-823 cells. Furthermore, the underlying mechanisms that restrain gastric cancer were evaluated by clone formation, EdU staining, flow cytometry, and other assays. Meanwhile, the role of TIPE2 in the anti-tumor effect of gracillin was elucidated via the use of siTIPE2 RNA. It was determined that gracillin could fight against gastric cancer cells by inhibiting the cell proliferation participated by the PI3K/AKT pathway and cell cycle arrest, suppressing the EMT pathway-regulating cell migration, and inducing bcl2-associated mitochondrial apoptosis. Additionally, TIPE2 maybe contribute to the benefits of gracillin. These results of the present study are an important step toward the medicinal development of gracillin, and are also of use in understanding the effect of TIPE2 as a potential tumor target.
Chronic Budd–Chiari syndrome (BCS) is a rare cause of liver cirrhosis (LC) and tends to be misdiagnosed in clinical practice. In order to characterize LC caused by chronic BCS, we conducted this retrospective observational study. Medical records of all patients who were initially diagnosed as chronic BCS with LC when discharged from our department from January, 2011 to October, 2016 were reviewed. Cirrhotic patients with known causes and cases lacked key data were excluded. Data of remaining patients was collected and analyzed. A total of 15 cases were included in this study. Patients with LC caused by chronic BCS were characterized by preserved liver function and prominent portal hypertension (PH). Abdominal distention and edema of lower extremities were most common initial manifestations. Intra- or extrahepatic collaterals on imaging studies were of great importance for differential diagnosis. Most of these patients received interventional angioplasty followed by anticoagulation with warfarin and survived without obvious complications of PH. Chronic BCS was a rare but important cause of LC and should always be considered in patients with chronic liver disease and so-called cryptogenic LC. Early diagnosis and timely treatment may improve outcome. Correct interpretation of imaging examinations was fundamental to avoiding misdiagnosis.
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