Determine changes of lncRNAs expression in malignant hepatocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Wei-Hua Xu
PROVIDER: E-GEOD-56384 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Long noncoding RNAs (lncRNAs) are a class of non-coding RNAs longer than 200 nt that function in endogenous gene regulation and tumorigenesis. Hepatocellular carcinoma (HCC) is a heterogeneous disease with different treatment outcome. It is a challenge to develop a prognostic marker to identify HCC patients who are at greatest risk for recurrence or death. In this study, we try to screen lncRNAs whose expression levels are associated with recurrence or death of HCC patients through an extensive lncRNA profiling study on a cohort of 59 HCC patients. For these experiments, we used RNA extracted from 59 HCC tissues and 20 normal livers. Total RNAs from the 20 normal livers were pooled and used as a reference for all microarray experiments. For each microarray experiment, Cy5-labeled probes derived from the DNase-treated total RNA from each HCC sample was hybridized against Cy3-labeled probes derived from common reference on Arraystar Human LncRNA Microarray (Arraystar, Rockville, USA). LncRNAs whose expression was significantly associated with disease-specific survival and time to recurrence were selected based on microarray data. The univariate Cox proportional hazards model was used to assess the association of lncRNAs with survival. We computed a statistical significance level (P value) for two endpointsM-bM-^@M-^Tthe time to cancer-related death and time to recurrence, based on univariate Cox proportional hazards models in BRB-ArrayTools version 4.2.0.
2012-08-16 | E-GEOD-40144 | biostudies-arrayexpress
Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling of lncRNAs expression profile in sorafenib resistant hepatocellular carcinoma cells. We identified 1240 differentially expressed lncRNAs with 576 up-regulated and 664 down-regulated (fold change > 2, P < 0.05) in sorafenib-resistant (HUH7-S) HCC cells (fold change > 2, P < 0.05) in sorafenib-resistant (HepG2-S) HCC cells, compared to parental sorafenib-sensitive (HUH7, HepG2) HCC cells by high-throughput sequencing. In addition, based on GO (Gene Ontology) term enrichment analysis, these differentially expressed lncRNAs are mainly related to binding and catalytic activity and biological regulation of metabolic processes in both the Huh7-S and HepG2-S cell lines compared to parental cell lines. Moreover, the differentially expressed genes analyzed by KEGG (Kyoto Encyclopedia of Genes and Genomes) Pathway were significantly related to tight junction. Among them, TCONS_00284048 and TCONS_00006019 expression were consistently up-regulated in resistant HCC cells, whereas both of them knock down increased the sensitivity of Huh7-S and HepG2-S cells to sorafenib.
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Project description:HCC cell lines with different metastatic potential (HepG2, Huh7, MHCC97 and PVTT cells) were treated with TGFbeta1 for 8 h We used microarrays to discover the long non-coding RNAs (lncRNAs) expression underlying Hepatocellular carcinoma (HCC) TGFbeta1 treated and non-treated control cells to identify distinct lncRNAs during this process.
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Project description:Hepatocellular carcinoma (HCC) is a frequent cancer with poor prognosis and with limited possibilities for anti-cancer treatment. Evidence has recently accumulated suggesting that multiple signaling pathways are activated in human cancer. It has been recently shown by exosome sequencing of HCC that 161 putative driver genes are associated with 11 recurrently altered pathways, suggesting that we need to inhibit these multiple pathways for HCC therapy. THOC5, a member of transcription/export (TREX) complex, that plays a role in less than 1% of mRNA processing in normal cells such as fibroblasts or macrophages, is not required for maintenance of mature hepatocytes. In this study, we have examined the role of THOC5 in human HCC. Enhanced THOC5 expression was not observed in differentiation grading 1 (G1) human HCC, but 78% of G2 and G3 exhibited increased levels of THOC5. Furthermore, the 50% depletion of THOC5 in hepatocellular carcinoma cell lines, Huh7 and HepG2 causes lipid accumulation and apoptosis. Transcriptome analysis using THOC5 depleted Huh7 and HepG2 cells revealed that 1049 and 837 genes were downregulated upon depletion of THOC5 in Huh7 and HepG2 cells, respectively. Among these genes, 396 were commonly downregulated in both cell lines. Some of these, such as tissue inhibitor of metalloproteinase 3 (TIMP3), tripartite motif containing 24 (TRIM24), ribosomal protein S6 kinase polypeptide 3 (RPS6KA3) and transmembrane emp24-like trafficking protein 10 (TMED10) are known to be fine tuners for several signal transduction pathways. The expression of these proteins was correlated with the THOC5 expression level in HCC. To inhibit multiple signaling pathways we are currently examining the effects of a combination of siRNAs against THOC5 target genes in HCC cell lines. Our data suggest that THOC5, which controls a set of genes that are involved in HCC malignancy can be a potential biomarker for HCC. In addition, THOC5 target gene, TMED10 may also be a novel biomarker of HCC. Furthermore, the suppression of the THOC5 gene per se or multiple THOC5 target genes may represent a novel strategy for cancer therapy. Huh7 and HepG2 cells were infected with lentiviral THOC5 and control shRNAs. Five days after infection, total RNAs were isolated and subjected to microarray analysis.
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Project description:Liver regeneration has important implications because many therapeutic strategies for the surgical treatment of liver diseases, such as removal of liver tumors and liver transplantation, depend on the ability of the liver to regenerate physically and functionally. Recent studies reported that lncRNAs control cell proliferation in hepatocellular carcinoma (HCC). However, the role of lncRNAs in liver regeneration and the overall mechanisms remain largely unknown. To address this issue, we carried out a genome-wide lncRNA microarray analysis during liver regeneration in mice after 2/3 partial hepatectomy (PH) at various time points. The results revealed differential expression of thousands of lncRNAs during liver regeneration. Six-week-old male wildtype C57Bl/6 mouse liver samples were obtained at 0, 1.5, 12, and 24 hours after 2/3 PH, and three mice were analyzed for each time point. Total RNA was isolated using Trizol.Mouse Stringent LncRNA Array (4 x 44K, ArrayStar, Rockville, MD) were used to monitor the expression level of approximately 14000 lncRNAs identified from the NCBI RefSeq, UCSC, RNAdb2.0, NRED, Fantom3.0 and UCRs. LncRNAs differentially expressed were identified by comparing expression levels during liver regeneration in mice after 2/3 partial hepatectomy (PH) at various time points.
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Project description:Molecular targeted therapy has shown promise as a treatment for advanced hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, recently received FDA approval for the treatment of advanced HCC. However, although sorafenib is well tolerated, concern for its safety has been expressed. Celecoxib (CelebrexM-BM-.) is a selective cyclooxygenase-2 (COX-2) inhibitor wich exhibits antitumor effects in human HCC cells. The present study examined the interaction between celecoxib and sorafenib in two human liver tumor cell lines HepG2 and Huh7. Our data showed that each inhibitor reduced cell growth and the combination of celecoxib with sorafenib synergistically inhibited cell growth and increased apoptosis. To better understand the molecular mechanisms underlying the synergistic antitumor activity of combination, we investigated the expression profile of the combination-treated liver cancer cell lines, using microarray analysis. Combination treatment significantly altered expression levels of 1,986 and 2,483 transcripts in HepG2 and Huh7 cells, respectively. Genes, functionally involved in cell death, signal transduction and regulation of transcription were predominantly up-regulated, while genes implicated in metabolism, cell cycle control and DNA replication and repair were mainly down-regulated upon treatment. However, combination-treated HCC cell line displayed specificity in the expression and activity of crucial factors involved in hepatocarcinogenesis. The altered expression of some of these genes was confirmed by semiquantitative and quantitative RT-PCR and by Western blotting. Many novel genes emerged from our transcriptomics analyses, and further functional analyses may determine whether these genes can serve as potential molecular targets for more effective anti-HCC strategies. To identify new potential mechanisms of combined action of celecoxib and sorafenib, their effects on global gene expression in both cell lines were investigated and compared using the DNA microarray technology. Agilent 44K Human Whole Genome Oligonucleotide Microarrays (containing ~44,000 genes) were used to identify global gene expression changes in the HepG2 and Huh7 hepatocellular carcinoma (HCC) cell lines, following simultaneous treatment with 50 M-BM-5M celecoxib and 7.5 M-BM-5M sorafenib for 48 hours. All microarray experiments (a total of four) were performed in duplicates applying dye-swaps to avoid labeling bias.
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