Identification and integrative analysis of microRNAs and mRNAs involved in proliferation and invasion in mechanical pressure-treated human hepatocellular carcinoma cell lines
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE119881 | GEO | 2020/04/10
REPOSITORIES: GEO
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Project description:The pressure changes in hepatic microenvironment may be involved in the regulation of proliferation and invasion of hepatocellular carcinoma, but the mechanism is unknown. This project simulates the mechanical microenvironmental conditions of liver cirrhosis, exerts the static water pressure on human hepatoma cell lines，and observes the changes of proliferation and invasion of hepatoma cells under different pressure loading conditions. Then screens the differential expression mechanic-responsive mRNAs under the optimal loading condition and carry out biological verification. Bioinformatics analysis was used to explore the related pathways. This study provides a theoretical basis for the prevention and treatment of liver cancer and provides a direction for finding effective drugs for clinical treatment of liver cancer.
2020-04-10 | GSE120194 | GEO
Project description:Tumor initiation and progression are critically dependent on interaction of cancer cells with their cellular and extracellular microenvironment. Alterations in the composition, integrity, and mechanical properties of the extracellular matrix (ECM) dictate tumor processes including proliferation, migration, and invasion. Also in primary liver cancers, consisting of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the dysregulation of the extracellular environment by liver fibrosis and tumor desmoplasia is pertinent. Yet, in-depth characterization of liver cancer ECM and underlying tumor-promoting mechanisms remain largely unknown. Herein, we used an integrative molecular and mechanical approach to extensively characterize the ECM of HCC and CCA tumors by utilizing decellularization techniques. We identified a myriad of ECM-related proteins in both tumor and adjacent liver tissue, highlighting the complexity of the primary liver cancer matrisome. The differences in ECM protein abundance result in divergent mechanical properties on a macro- and micro-scale that is tumor-type specific. Furthermore, we employed the decellularized tumor ECM to create a tumor-specific hydrogel that support patient-derived tumor organoids. This provides a new avenue for personalized medicine by combining patient-derived tumor ECM and cancer cells. Taken together, this study provides better understanding of alterations to key aspects of the ECM that occur during primary liver cancer development.
2023-03-28 | PXD035261 | Pride
Project description:With the aim to reveal the function of microRNAs in Hepatic stellate cells (HSCs) in response to portal hypertension, primary rat HSCs were exposed to pressure (10mmHg, 1 h) by using a pressure induced apparatus. Appling next-generation sequencing screened the pressurization induced miRNAs expression profile in HSCs. Among them miR-9a-5p was confirmed to be significantly increased after loading pressure in HSC by RT-PCR. It was found that inhibition of miR-9a-5p could significantly restrain HSCs proliferation and activation under pressure overload. Moreover, the results showed that the induction of miR-9a-5p upon pressure load might by increasing the phosphorylation of Akt but not FAK and Erk1/2. Luciferase reporter assay and western blot suggested that Sirt1 was a potential target gene of miR-9a-5p. Finally, we revealed that miR-9a-5p level was apparently higher in rat liver fibrotic model than in the normal control while Sirt1 level was decreased in fibrotic liver tissue. In conclusion, our results suggest that miR-9a-5p regulate HSCs proliferation through negative regulation of Sirt1 and suggest a potential biomarker for portal hypertension.
2017-08-29 | GSE63783 | GEO
Project description:Mechanical loading is a potent strategy to induce bone formation, but with aging, the bone formation response to the same mechanical stimulus diminishes. Our main objectives were to (i) discover the potential transcriptional differences and (ii) compare the periosteal cell proliferation between tibias of young-adult and old mice in response to strain-matched mechanical loading. First, to discover potential age-related transcriptional differences, we performed RNA sequencing (RNA-seq) to compare the loading responses between tibias of young-adult (5-month) and old (22-month) C57BL/6N female mice following 1, 3, or 5 days of axial loading (loaded versus non-loaded). Compared to young-adult mice, old mice had less transcriptional activation following loading at each time point, as measured by the number of differentially expressed genes (DEGs) and the fold-changes of the DEGs. Old mice engaged fewer pathways and gene ontology (GO) processes, showing less activation of processes related to proliferation and differentiation. In tibias of young-adult mice, we observed prominent Wnt signaling, extracellular matrix (ECM), and neuronal responses, which were diminished with aging. Additionally, we identified several targets that may be effective in restoring the mechanoresponsiveness of aged bone, including nerve growth factor (NGF), Notum, prostaglandin signaling, Nell-1, and the AP-1 family. Second, to directly test the extent to which periosteal cell proliferation was diminished in old mice, we used bromodeoxyuridine (BrdU) in a separate cohort of mice to label cells that divided during the 5-day loading interval. Young-adult and old mice had an average of 15.5 and 16.7 BrdU+ surface cells/mm, respectively, suggesting that impaired proliferation in the first 5 days of loading does not explain the diminished bone formation response with aging. We conclude that old mice have diminished transcriptional activation following mechanical loading, but periosteal proliferation in the first 5 days of loading does not differ between tibias of young-adult and old mice.
2020-09-10 | GSE157719 | GEO
Project description:Skeletal integrity in humans and animals is maintained by daily mechanical loading. It has been widely accepted that osteocytes function as mechanosensors. Many biochemical signaling molecules are involved in the response of osteocytes to mechanical stimulation. The aim of this study was to identify genes involved in the translation of mechanical stimuli into bone formation. The four-point bending model was used to induce a single period of mechanical loading (comprising 300 cycles (2 Hz) using a peak magnitude of 60 N) on the right tibia, while the contra lateral left tibia served as control. Six hours after loading, the effects of mechanical loading on gene-expression were determined with microarray analysis. Protein expression of differentially regulated genes was evaluated with immunohistochemistry. Nine genes were found to exhibit a significant differential gene expression in LOAD compared to control. MEPE, Garnl1, V2R2B, and QFG TN1 olfactory receptor were up-regulated, and creatine kinase (muscle form), fibrinogen-B beta-polypeptide, monoamine oxidase A, troponin-C and kinesin light chain-C were down-regulated. Validation with real-time RT-PCR analysis confirmed the up regulation of MEPE and the down-regulation of creatine kinase (muscle form) and troponin-C in the loaded tibia. Immunohistochemistry showed that the increase of MEPE protein expression was already detectable six hours after mechanical loading. In conclusion, these genes probably play a role during translation of mechanical stimuli six hours after mechanical loading. The modulation of MEPE expression may indicate a connection between bone mineralization and bone formation after mechanical stimulation. Two groups: LOAD vs contralateral control and SHAM vs contralateral control (n=5/group)
2013-11-21 | E-GEOD-50707 | biostudies-arrayexpress
Project description:The advent of high-throughput measurements of gene expression and bioinformatics analysis methods offers new ways to study gene expression patterns. The primary goal of this study was to determine the time sequence for gene expression in a bone subjected to mechanical loading, during key periods of the bone formation process, including expression of matrix-related genes, the appearance of active osteoblasts, and bone desensitization. A standard model for bone loading was employed in which the right forelimb was loaded axially for three minutes per day, while the left forearm served as a non-loaded, contralateral control. We evaluated loading-induced gene expression over a time course of 4 hours to 32 days after the first loading session. Six distinct, time-dependent patterns of gene expression were identified over the time course and categorized into three primary clusters: genes upregulated early in the time course, genes upregulated during matrix formation, and genes downregulated during matrix formation. Genes were then grouped based on function and/or signaling pathways. Many gene groups known to be important in loading-induced bone formation were identified within the clusters, including AP-1-related genes in the early response cluster, matrix-related genes in the upregulated gene clusters, and Wnt/?-catenin signaling pathway inhibitors in the downregulated gene clusters. Several novel gene groups were identified as well, including chemokine-related genes which were upregulated early but downregulated later in the time course, solute carrier genes which were both up- and downregulated, and muscle-related genes which were primarily downregulated. Time Course with 11 time points, each plus & minus mechanical stimulation with 5 replicates per experimental group (except 12d group which has 4 replicates). Daily mechanical loading was applied to the forearm (24 hours between loading sessions), and ulnae were sampled at indicated time points (4h, 12h, 1d, 2d, 4d, 6d, 8d, 12d, 16d, 24d, or 32d).
2010-06-12 | E-GEOD-22286 | biostudies-arrayexpress
Project description:Silymarin (SM) is a popular botanical medicine with purported liver protective effects. SM displays multiple effects in animal models and in cell culture including prevention of liver disease, reduction of inflammation, oxidative stress, and proliferation. Despite a plethora of data indicating that SM impinges on multiple cellular signaling pathways important in inflammation and disease, no unifying mechanisms have been forwarded. To define how SM elicits so many biological effects, the current study presents the first comprehensive transcriptional profiling study of human hepatoma cells treated with SM. The intention of the study was to focus on the early transcriptional events that are associated with SM-induced inhibition of proliferation and inflammation. Collectively, the data demonstrate that SM causes a rapid transcriptional reprogramming of cells that initially manifests as energy stress and slowing of cellular metabolism, leading to inhibition of cell growth and inflammation. The effects of silymarin on liver hepatoma Huh7.5.1 cells were detected using a time course approach.
2015-07-01 | E-GEOD-50994 | biostudies-arrayexpress
Project description:Even though liver kinase B1 (LKB1) is commonly described as a tumor suppressor, we and others have shown that LKB1 is augmented in liver cancer. In agreement, LKB1 modulation in human hepatoma cells and mouse livers induces changes in cell proliferation and the appearance of liver neoplastic lesions in association with disruptions of energetic metabolism. After LKB1 overexpression, a surprising uncoupling between LKB1 and its downstream kinase AMP-activated protein kinase is observed as well as activation of the oncogenic Ras pathway, driven by the direct or indirect binding of LKB1 to the promoter region of the Ras activator, RASGRP3. Under these circumstances, LKB1 SUMOylation at Lys178 by SUMO-2, the main SUMO paralogue present in liver, promotes LKB1 nuclear localization, fueling hepatoma cell proliferation. Overall, SUMO-2 mediated modification of LKB1 at Lys178 is suggested as a bona fide oncogenic driver in liver cancer by regulating the nucleo-cytoplasmic shuttling of LKB1.
2018-09-11 | GSE99584 | GEO
Project description:Skeletal integrity in humans and animals is maintained by daily mechanical loading. It has been widely accepted that osteocytes function as mechanosensors. Many biochemical signaling molecules are involved in the response of osteocytes to mechanical stimulation. The aim of this study was to identify genes involved in the translation of mechanical stimuli into bone formation. The four-point bending model was used to induce a single period of mechanical loading (comprising 300 cycles (2 Hz) using a peak magnitude of 60 N) on the right tibia, while the contra lateral left tibia served as control. Six hours after loading, the effects of mechanical loading on gene-expression were determined with microarray analysis. Protein expression of differentially regulated genes was evaluated with immunohistochemistry. Nine genes were found to exhibit a significant differential gene expression in LOAD compared to control. MEPE, Garnl1, V2R2B, and QFG TN1 olfactory receptor were up-regulated, and creatine kinase (muscle form), fibrinogen-B beta-polypeptide, monoamine oxidase A, troponin-C and kinesin light chain-C were down-regulated. Validation with real-time RT-PCR analysis confirmed the up regulation of MEPE and the down-regulation of creatine kinase (muscle form) and troponin-C in the loaded tibia. Immunohistochemistry showed that the increase of MEPE protein expression was already detectable six hours after mechanical loading. In conclusion, these genes probably play a role during translation of mechanical stimuli six hours after mechanical loading. The modulation of MEPE expression may indicate a connection between bone mineralization and bone formation after mechanical stimulation.
2013-11-21 | GSE50707 | GEO
Project description:BACKGROUND & AIMS: We performed an integrated analysis to identify microRNAs (miRNAs) and mRNAs with altered expression in liver tumors from 3 mouse models of hepatocellular carcinoma (HCC) and human tumor tissues. METHODS: We analyzed miRNA and mRNA expression profiles of liver tissues from mice with diethylnitrosamine-induced hepatocarcinogenesis, conditional expression of lymphotoxin alpha and lymphotoxin beta , or inducible expression of a Myc transgene (Tet-O-Myc mice), as well as male C57BL/6 mice (controls). miRNA mimics were expressed and miRNAs and mRNAs were knocked down in human (Huh7, Hep3B, JHH2) hepatoma cell lines; cells were analyzed for viability, proliferation, apoptosis, migration, and invasion. Cells were grown as xenograft tumors in nude mice and analyzed. We combined in-silico target gene prediction with mRNA profiles from all 3 mouse models. We quantified miRNA levels in 146 fresh-frozen tissues from patients (125 HCCs, 17 matched non-tumor tissues, and 4 liver samples from patients without cancer) and published human data sets and tested correlations with patient survival times using Kaplan-Meier curves and the log-rank test. Levels of NUSAP1 mRNA were quantified in 237 HCCs and 5 non-tumor liver samples using the Taqman assay. RESULTS: Levels of the microRNA 193a-5p (MIR193A-5p) were reduced in liver tumors from all 3 mouse tumor models and in human HCC samples, compared with non-tumor liver tissues. Expression of a MIR193A-5p mimic in hepatoma cells reduced proliferation, survival, migration, and invasion and their growth as xenograft tumors in nude mice. We found nucleolar and spindle associated protein 1 (NUSAP1) to be a target of MIR193A-5p; HCC cells and tissues with low levels of MIR193A-5p had increased expression of NUSAP1. Increased levels of NUSAP1 in HCC samples correlated with shorter survival times of patients. Knockdown of NUSAP1 in Huh7 cells reduced proliferation, survival, migration, and growth as xenograft tumors in nude mice. Hydrodynamic tail-vein injections of a small hairpin RNA against NUSAP1 reduced growth of AKT1-MYC-induced tumors in mice. CONCLUSIONS: MIR193A-5p appears to prevent liver tumorigenesis by reducing levels of NUSAP1. Levels of MIR193A-5p are reduced in mouse and human HCC cells and tissues, leading to increased levels of NUSAP1, associated with shorter survival times of patients. Integrated analyses of miRNAs and mRNAs in tumors from mouse models can lead to identification of therapeutic targets in humans.
2018-09-19 | GSE102416 | GEO