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Oncotarget a primarily oncology-focused, peer-reviewed, open access, weekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.
Its scope is unique. The term "oncotarget" encompasses all molecules, pathways, cellular functions, cell types, and even tissues that can be viewed as targets relevant to cancer as well as other diseases. The term was introduced in the inaugural Editorial Introducing OncoTarget. Sponsored Conferences. Bing He, email: hebinghb mail. Hu-Qin Zhang, email: huqzhang mail.
In HCC cell lines, the miRP suppressed cell proliferation by inhibiting the transformation G1 phase to S phases of the cell cycle. The experiments in animal model implied miRP could be a potential therapeutic agent for HCC in the future.
Hepatocellular carcinoma HCC is the second leading cause of cancer-related death of human [ 1 , 2 ]. Various high-throughput transcriptomics studies were performed to investigate potential key regulating miRNAs in the pathogenesis of HCC [ 5 , 6 ].
Fold change and T-test were most common used methods to select candidate miRNAs in these studies. The miRNAs participate the pathogenesis of HCC by inhibiting their target genes in a complex molecular network [ 7 - 9 ]. Further in vitro and in vivo experiments confirmed our prediction and found that miRP inhibits the proliferation and invasion of HCC cells by inhibiting polycomb protein EED.
Moreover, the results of this study also revealed that low level of miRP is associated with poor prognosis of HCC patients and implied that miRP could be a potential therapeutic agent for HCC in the future. There are four key variables in MNBO: the differentially expression of miRNA, the number of its targets, the differentially expression and network importance degree of every target.
Among these new candidates reported by MNBO, the roles of miR [ 11 , 12 ], miR [ 13 ] and miRA-5P [ 14 ] in the pathogenesis of HCC have been confirmed by previous studies, while that of miRP was still ambiguous by conflicting reports [ 15 , 16 ]. To examine whether miRP is a false discovery, we made further investigations on it with a larger population of HCC patients. The size of the node represent miRNA target is determined by the network influence.
The larger size represents one with more importance. Major target is the target that has the largest network influence among all the targets of one miRNA.
Prognosis is very important for HCC patients. The miRP high group had a significantly higher survival rate than the miRP low group, based on disease-free survival curves from Kaplan—Meier analysis Figure 2B. The major target is the target that has the largest network influence, which is calculated by evaluating interacting neighbors and differential expressions in HCC see methods.
EED protein levels were significant higher T. This phenomenon was associated with a concomitant decrease of cells at the S phases of the cell cycle Figure 4C and 4D.
Moreover, the percentage of miRP-inhibitors-transfected at G1 phase decreased comparing to control cells. And it was associated with a concomitant increase of cells at the S phases of the cell cycle Figure 4C and 4D.
These evidences suggested that miRP blocks the cell cycle progress and inhibits cell proliferation via EED. Cell migration and invasion are key progresses in tumor metastasis, which is the main reason for poor survival of HCC patients [ 17 ]. Transwell migration assay and Matrigel invasion assay revealed that the cell migration and invasion were inhibited in miRP-mimics-transfected and EED -siRNAs-transfected cells compared with inactive-control-transfected cells Figure 5.
To investigate the relationship between miRP and tumorigenesis in vivo , the xenograft model of HepG2 cells in nude mice was adopted. HepG2 cells that stably expressed miRP, miRP inhibitors, or their controls were injected subcutaneously into each flank of nude mice. The tumor weights and volumes were monitored. Then the growth curves of the tumors were plotted accordingly.
We found that miRP overexpression significantly decreased tumor growth and miRP inhibitors promoted it in vivo Figure 6. These in vivo observations confirmed the key role of miRP in the tumor growth of HCC and may serve as a potential therapeutic agent for HCC in the future.
A Growth curves of xenograft in nude mice after the injection of HepG2 cells stably expressing miRP and controls; B growth curves of xenograft in nude mice after the injection of HepG2 cells stably expressing miRP inhibitors and controls; C quantification of tumor weights of xenograft tumors in mice injection of HepG2 cells stably expressing miRP and controls; D quantification of tumor weights of xenograft tumors in mice injection of HepG2 cells stably expressing miRP inhibitors and controls;.
Hepatocellular carcinoma HCC is the second leading cause of cancer-related death worldwide [ 1 , 2 ]. The regulating roles of miR [ 11 , 12 ], miR [ 13 ] and miRA-5P [ 14 ] in the pathogenesis of HCC have been confirmed by previous studies, while that of miRP was still ambiguous by two conflicting reports [ 15 , 16 ].
To examine whether miRP is a false discovery, we made further investigations on it. Further in vivo experiments confirmed the key regulating role of miRP in the tumor growth of HCC and implied it could be a potential therapeutic agent for HCC Figure 6. The miRP suppresses malignant biological behaviors of glioblastoma stem cells [ 18 ] and cancer cell migration, invasion and epithelial-mesenchymal transition in glioblastoma [ 19 ].
In this study, we found miRP inhibits cell cycle, proliferation, invasion and migration via EED in vitro , and suppresses tumor growth in vivo. Cell invasion and migration, as well as epithelial-mesenchymal transition are key progresses in tumor metastasis [ 17 ], which is leading reason for death of HCC patients [ 22 ].
It may partially explain the mechanisms of why low expression of miRP is associated with poor survival of HCC patients. This method will be a useful tool for selecting candidate miRNAs for wet-experiments in future cancer studies. The molecular network used in this study was constructed by two parts: interactions between miRNA and gene during the transcription, and interactions among transcription products of genes.
The miRNA-target interactions supported by at least one wet-experiment method or two prediction methods were included into the selection process using expression pattern. Since miRNAs target genes and inhibit their expression, the expression pattern of a miRNA and its target gene should be opposite. Interactions among transcription products of the genes expressed in HCC were identified using protein-protein interaction data downloaded from the BioGRID database [ 28 ] version 3.
The algorithm is described as follows:. E H is the average expression value of a miRNA in matched healthy controls. E Ci is the average expression value of target i in HCC patients.
E Hi is the average expression value of target i in matched healthy controls. D i is the degree of target i in the molecular network of HCC.
A total of patients with HCC were enrolled. Informed consents were obtained from all participants. Survival of HCC patients were analyzed by tracking patients. The disease-free survival curves were estimated using the Kaplan—Meier method and compared with Log-rank Mantel-Cox test. Single serial sections were made from xenograft tumor samples. Then the slides were incubated with HRP-conjugated goat anti—mouse secondary antibodies. The proteins were visualized in situ with DAB chromogenic substrate.
The renilla and firefly luciferase activities were measured by a dual luciferase assay Promega, Beijing, China at 24 h after transfections. After extensive washes, the secondary antibody Abcam, Beijing, China was added to the system. Enhanced chemiluminescence was used for detection of EED. Proliferation rate was measured at 24h, 48h and 72h after transfection. Then cells were stained with propidium iodide. Cell cycle was determined by flow cytometry. Cell invasion and migration were detected using transwell chamber assays Corning, Beijing, China with or without Matrigel Life Technologies, Beijing, China.
After that cells on the bottom surface of the membrane were fixed and stained with the 0. The temperature was well controlled. And the water and food were well supplied. The rats were acclimatized to the conditions of the animal house for at least seven days before they were used in experiments. Mice were monitored every three day and euthanized one month later. Then tumors were dissected and weighed.
Experiments were repeated at least three times to achieve confident results. Statistical analysis was performed using R. When comparing repeated measured outcomes in time series groups, repeated-measures ANOVA was used for analyzing the data.
The linear regression was used to determine correlations between variables. Statistical analysis was considered to be significant when P. International journal of cancer. Flores A, Marrero JA. Emerging trends in hepatocellular carcinoma: focus on diagnosis and therapeutics. Clinical Medicine Insights Oncology. Bartel DP. MicroRNAs: target recognition and regulatory functions.
Early-phase circulating miRNAs predict tumor recurrence and survival of hepatocellular carcinoma patients after liver transplantation. Involvement of inflammation and its related microRNAs in hepatocellular carcinoma. HCCNet: an integrated network database of hepatocellular carcinoma. Cell Res. Combination therapeutics in complex diseases. J Cell Mol Med. A comprehensive analysis of the dynamic biological networks in HCV induced hepatocarcinogenesis. PLoS One. Sci Rep.
Biochem Biophys Res Commun. MicroRNAs regulate methionine adenosyltransferase 1A expression in hepatocellular carcinoma. J Clin Invest.
Methods to Study Trinucleotide Repeat Instability Induced by DNA Damage and Repair.
Oncotarget a primarily oncology-focused, peer-reviewed, open access, weekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Its scope is unique. The term "oncotarget" encompasses all molecules, pathways, cellular functions, cell types, and even tissues that can be viewed as targets relevant to cancer as well as other diseases. The term was introduced in the inaugural Editorial Introducing OncoTarget. Sponsored Conferences. Bing He, email: hebinghb mail.
Identifying key regulating miRNAs in hepatocellular carcinomas by an omics' method
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