Anti-miR-21 Suppresses Hepatocellular Carcinoma Growth via Broad Transcriptional Network De-regulation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE65892 | GEO | 2015/03/24
SECONDARY ACCESSION(S): PRJNA275315
REPOSITORIES: GEO
Similar Datasets
Project description:Primary hepatic tumors mainly include hepatocellular carcinoma (HCC), which is one of the most frequent causes of cancer-related deaths worldwide. Thus far, HCC prognosis has remained extremely poor given the lack of effective treatments. Numerous studies have described the roles played by microRNAs (miRNAs) in cancer progression and the potential of these small noncoding RNAs for diagnostic or therapeutic applications. The current consensus supports the idea that direct repression of a wide range of oncogenes by a single key miRNA may critically affect the malignant properties of cancer cells in a synergistic manner. In this study, we aimed to investigate the oncogenes controlled by miR-493-5p, a major tumor suppressor miRNA that inactivates miR-483-3p oncomir in hepatic cancer cells. Using global gene expression analysis, we highlighted a set of candidate genes potentially regulated by miR-493-5p. In particular, the canonical MYCN proto-oncogene (MYCN) appeared to be an attractive target of miR-493-5p given its significant inhibition via 3’-UTR targeting in miR-493-5p-rescued HCC cells. We showed that MYCN was overexpressed in liver cancer cell lines and clinical samples from HCC patients. Notably, MYCN expression levels were inversely correlated with miR-493-5p in tumor tissues. We confirmed that MYCN knockdown mimicked the anti-cancer effect of miR-493-5p by inhibiting HCC cell growth and invasion, whereas MYCN rescue hindered miR-493-5p activity. In summary, miR-493-5p is a pivotal miRNA that modulates various oncogenes after its re-expression in liver cancer cells, suggesting that tumor suppressor miRNAs with a large spectrum of action may provide valuable tools for miRNA replacement therapies.
2019-01-22 | GSE125407 | GEO
Project description:We profiled miRNA expression in tissue samples (104 HCC, 90 adjacent cirrhotic livers, 21 normal livers) as well as in 35 HCC cell lines. A set of 12 miRNAs (including miR-21, miR-221/222, miR-34a, miR-519a, miR-93,miR-96, and let-7c) was linked to disease progression from normal liver through cirrhosis to full-blown HCC. miR-221/222, the most upregulated miRNAs in tumor samples, are shown to target the CDK inhibitor p27 and to enhance cell growth in vitro. Conversely, these activities can be efficiently inhibited by an antagomiR specific for miR-221. In addition, we show, using a mouse model of liver cancer, that miR-221 overexpression stimulates growth of tumorigenic murine hepatic progenitor cells.
2009-12-08 | E-TABM-866 | biostudies-arrayexpress
Project description:Numerous studies have described the critical role played by microRNAs (miRNAs) in cancer progression and the potential of these small non-coding RNAs for diagnostic or therapeutic applications. However, the mechanisms responsible for the altered expression of miRNAs in malignant cells remain poorly understood. Herein, via epigenetic unmasking, we identified a group of miRNAs located in the imprinted delta like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3 (MEG3) locus that were repressed in hepatic tumor cells. Notably, miR-493-5p epigenetic silencing was correlated with hypermethylation of the MEG3-differentially regulated region (DMR) in liver cancer cell lines and tumor tissues from patients. Experimental rescue of miR-493-5p promoted an anti-cancer response by hindering hepatocellular carcinoma (HCC) cell growth in vitro and tumor progression in vivo. We found that miR-493-5p mediated part of its tumor-suppressor activity by abrogating overexpression of insulin-like growth factor 2 (IGF2) and the IGF2-derived intronic oncomir miR-483-3p in HCC cells characterized by IGF2 loss of imprinting (LOI). In summary, this study describes an unknown miRNA-dependent regulatory mechanism between two distinct imprinted loci and a possible therapeutic window for liver cancer patients exhibiting IGF2-miR-483 LOI and amplification.
2018-12-05 | GSE123314 | GEO
Project description:Numerous studies have described the critical role played by microRNAs (miRNAs) in cancer progression and the potential of these small non-coding RNAs for diagnostic or therapeutic applications. However, the mechanisms responsible for the altered expression of miRNAs in malignant cells remain poorly understood. Herein, via epigenetic unmasking, we identified a group of miRNAs located in the imprinted delta like non-canonical Notch ligand 1 (DLK1)-maternally expressed 3 (MEG3) locus that were repressed in hepatic tumor cells. Notably, miR-493-5p epigenetic silencing was correlated with hypermethylation of the MEG3-differentially regulated region (DMR) in liver cancer cell lines and tumor tissues from patients. Experimental rescue of miR-493-5p promoted an anti-cancer response by hindering hepatocellular carcinoma (HCC) cell growth in vitro and tumor progression in vivo. We found that miR-493-5p mediated part of its tumor-suppressor activity by abrogating overexpression of insulin-like growth factor 2 (IGF2) and the IGF2-derived intronic oncomir miR-483-3p in HCC cells characterized by IGF2 loss of imprinting (LOI). In summary, this study describes an unknown miRNA-dependent regulatory mechanism between two distinct imprinted loci and a possible therapeutic window for liver cancer patients exhibiting IGF2-miR-483 LOI and amplification.
2018-12-05 | GSE123313 | GEO
Project description:The goal of this experiment was to identify possible genes affected directly or indirectly by anti-miR-191. Hepatocellular carcinoma (HCC) is a fatal disease with currently very limited beneficial therapies. MicroRNAs (miRs), which are considered to be master regulators of gene expression, have significant influence on cellular pathways and phenotype, and are de-regulated in HCC, and hence are thought to be of great therapeutic potential as novel targets. We identified hsa-miR-191 as a potential target for HCC therapy. Inhibition of this miR causes decreased cell proliferation and induction of apoptosis in vitro as well as a significant reduction of tumor mass in vivo in an orthotopic liver xenograft model. This miR was also found to be up-regulated by a dioxin, a known liver carcinogen, and was found to be a key regulator of cancer related pathways. HCC cell line treated with anti-miR-191, and treated with negative control anti-miR. Treatment was done twice (duplicates) but in independent studies.
2011-07-01 | E-GEOD-22790 | biostudies-arrayexpress
Project description:The goal of this experiment was to study the effectivity of miR down regulation by using an anti-miR molecule. Hepatocellular carcinoma (HCC) is a fatal disease with currently very limited beneficial therapies. MicroRNAs (miRs), which are considered to be master regulators of gene expression, have significant influence on cellular pathways and phenotype, and are de-regulated in HCC, and hence are thought to be of great therapeutic potential as novel targets. We identified hsa-miR-191 as a potential target for HCC therapy. Inhibition of this miR causes decreased cell proliferation and induction of apoptosis in vitro as well as a significant reduction of tumor mass in vivo in an orthotopic liver xenograft model. This miR was also found to be up-regulated by a dioxin, a known liver carcinogen, and was found to be a key regulator of cancer related pathways. HCC cell line treated with anti-miR-191, and treated with negative control anti-miR. Although this experiment was done with dual channel, chanels are not compared, irrelevant samples were on the reciprocal channel. Sample data tables represent relevant, single channel data.
2011-07-01 | E-GEOD-22793 | biostudies-arrayexpress
Project description:Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide, reflecting the need for a better understanding of hepatocarcinogenesis. In this study, we examined the genome-wide expression profiles of both miRNAs and mRNAs from paired tumor and adjacent non-tumor tissues from a cohort of 96 HCC patients in Hong Kong where hepatitis B virus (HBV) is endemic. The comprehensive analysis of the coordinate expression of miRNAs and mRNAs reveals that miR-122 is under-expressed in HCC and that it is an important regulator for normal mitochondrial metabolism. A decreased level of miR-122 leads to an increase in expression of miR-122 seed-matched genes, a loss of mitochondrial metabolic function, and a decrease in the expression of many miR-122 secondary targets. These secondary targets are prognostic markers for HCC patients. Transcriptome profiling data from an additional 180 HCC and 40 liver cirrhotic patients in the same cohort were used to confirm the anti-correlation of miR-122 primary and secondary target gene sets. To test the HCC findings in normal mouse liver, we used an antagomir against miR-122 and identified altered gene expression profiling by microarray analysis in mouse in vivo experiments. The mouse data recapitulated the human HCC findings. Our anti-miR122 data further provided a direct link between increases in the mRNA levels of miR-122 controlled genes and impairments of mitochondrial metabolism. In summary, we find miR-122 loss may be detrimental to mitochondrial-related metabolisms in sustaining critical liver function and contribute to the morbidity and mortality of liver cancer patients. Mouse liver profiling: In one treatment regimen, four animals were given four doses of 100mg ASO/kg body weight, administered every other day, and sacrificed one day after the last dose. Four animals treated for four weeks were treated twice weekly with 50mg ASO/kg body weight, and sacrificed two days after the last dose. Mice were sacrificed in the morning, and liver was removed for further analysis. Samples from oligonucleotide-treated mice were referenced against samples from saline-treated mice in fluor-reversed pairs. Human liver profiling: For human HCC patient samples, 192 samples -- 96 resected tumor and 96 adjacent non-tumor liver tissues -- were collected from 96 patients who had undergone hepatectomy for curative treatment of HCC at Queen Mary Hospital, Pokfulam, Hong Kong between 1990 and 2007. Informed consents were obtained from patients regarding the use of the liver specimens for research. Samples were hybridized to Affymetrix arrays for mRNA profiling and were analyzed by quantitative PCR for microRNA profiling.
2010-06-09 | E-GEOD-22058 | biostudies-arrayexpress
Project description:Ηepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Early de-tection/diagnosis is vital for the prognosis of HCC whereas diagnosis at late stages is associated with very low survival rate. Early diagnosis is based on patient’s 6 month surveillance and use of at least two imaging modalities. The aim of this study was to investigate diagnostic markers for the detection of early HCC based on proteome analysis, microRNAs (miRNAs) and circulat-ing tumor cells (CTCs) in the blood of patients with cirrhosis, early and advanced HCC. We studied 89 patients with HCC of whom 33 had early HCC and 28 cirrhotic patients. CTCs were detected by Real-Time Quantitative Reverse Transcription PCR and immunofluorescence using the markers Epithelial cell adhesion molecule (EPCAM), Vimentin, A Fetoprotein (AFP) and surface major Vault protein (sMVP). Expression of the five most commonly HCC-involved miRNAs (miR-122, miR-200a, miR-200b, miR-221, miR-222) was examined in the serum by qRT-PCR. Finally patient serum was analyzed by whole proteome analysis (LC/MS). Twenty seven out of 53 (51%) patients with advanced HCC had detectable CTCs. Among them, 10/27 (37%) presented evidence of mesenchymal or intermediate stage cells (vimentin and/or sMVP positive). Moreover, 5/17 (29%) patients with early HCC and 6/28 (21%) cirrhotic patients had detectable CTCs. Patients with early and advanced HCC exhibited a significant increase of miR-200b when compared to cirrhotic patients. Our proteome analysis indicated that early HCC patients present a significant upregulation of APOA2, APOC3 proteins when compared to cir-rhotic patients, that when used in combination, cover the 100% of the patients with early HCC. In conclusion, miR-200b, APOA2 and APOC3 proteins are sensitive markers and can be poten-tially useful in combination for the early diagnosis of HCC.
2023-03-11 | PXD033306 | Pride
Project description:In vivo oncomiR screen identifies miR-21* independent of miR-21 as a driver in skin cancer
| PRJNA281170 | ENA
Project description:Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide, reflecting the need for a better understanding of hepatocarcinogenesis. In this study, we examined the genome-wide expression profiles of both miRNAs and mRNAs from paired tumor and adjacent non-tumor tissues from a cohort of 96 HCC patients in Hong Kong where hepatitis B virus (HBV) is endemic. The comprehensive analysis of the coordinate expression of miRNAs and mRNAs reveals that miR-122 is under-expressed in HCC and that it is an important regulator for normal mitochondrial metabolism. A decreased level of miR-122 leads to an increase in expression of miR-122 seed-matched genes, a loss of mitochondrial metabolic function, and a decrease in the expression of many miR-122 secondary targets. These secondary targets are prognostic markers for HCC patients. Transcriptome profiling data from an additional 180 HCC and 40 liver cirrhotic patients in the same cohort were used to confirm the anti-correlation of miR-122 primary and secondary target gene sets. To test the HCC findings in normal mouse liver, we used an antagomir against miR-122 and identified altered gene expression profiling by microarray analysis in mouse in vivo experiments. The mouse data recapitulated the human HCC findings. Our anti-miR122 data further provided a direct link between increases in the mRNA levels of miR-122 controlled genes and impairments of mitochondrial metabolism. In summary, we find miR-122 loss may be detrimental to mitochondrial-related metabolisms in sustaining critical liver function and contribute to the morbidity and mortality of liver cancer patients.
2010-06-09 | GSE22058 | GEO