EGAS00001003536 - samples
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ABSTRACT:
PROVIDER: EGAD00001004938 | EGA |
REPOSITORIES: EGA
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Project description:Hepatocellular carcinoma (HCC) is a heterogeneous aggressive malignancy with low efficacy of current therapies at advanced stages. We integrated molecular and pharmacological profiling of a large panel of liver cancer cell lines (LCCL) to assess their clinical relevance as HCC preclinical models and identify new effective therapies and biomarkers of response. We performed multi-omic analysis including whole-exome, RNA and miRNA sequencing and quantification of 126 proteins in a series 34 LCCL coupled with a screening of 29 anti-cancer agents. Molecular profiles of LCCL and primary HCC were compared and we searched for molecular features associated with drug response. Our panel of LCCL faithfully recapitulated the most aggressive molecular "proliferation class" of HCC. Genomic alterations of the RAS-MAPK pathway correlated with trametinib sensitivity that was more potent than FGFR4 inhibitors in tumor cells depending on the FGF19/FGFR4 pathway. Moreover, we showed that FGF19 amplification was only functional in tumor cells that retained a hepatocyte differentiation program with expression of FGFR4, KLB and NR1H4 highlighting the complex interplay between the genomic and transcriptomic context in drug response. We also identified drugs/combination that could target efficiently the transcriptomic "progenitor subclass of HCC", as well as specific genetic contexts such as inactivating mutations in TSC1/TSC2 and TP53 associated with higher sensitivity to the mTOR inhibitor rapamycin and the AURKA inhibitor alisertib, respectively. LCCL represent relevant preclinical models for drug-biomarker discovery in HCC and enabled to identify molecular contexts linked with particular therapeutic vulnerabilities that may be useful to stratify patients in future clinical trials
| EGAS00001003536 | EGA
Project description:Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor due to activation of multiple cellular pathways and molecular alterations. Herein, we report the first molecular classification of 89 HCC based on the expression of 358 microRNAs and integrative genomic analysis. Three main subclasses of HCC were identified : two of them were associated with beta-catenin mutations or aggressive phenotype. A subset of the subclass of aggressive tumors (8/89, 9%) showed overexpression of a cluster of microRNAs located on chr19q13.41 (C19MC locus. We showed that miR 517a, representing C19MC, promoted cell proliferation, migration and invasion in vitro and induced the development of aggressive tumors in vivo suggesting its role as a novel oncogenic driver in HCC. This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2011-02-17 | E-GEOD-20596 | biostudies-arrayexpress
Project description:Background: The identification of new high sensitivity and specificity markers for HCC are essential. We aimed to identify serum microRNAs for diagnosing hepatitis B virus (HBV) â??related HCC. Methods: Serum microRNA expression was investigated with four cohorts including 667 participants (261 HCC patients ,233 cirrhosi patients and 173 healthy controls), recruited between August 2010 and June 2013. First, An initial screening of miRNA expression by Illumina sequencing was performed using serum samples pooled from HCC patients and controls,respectively. Quantitative reverse-transcriptase polymerase chain reaction assay was then applied to evaluate the expression of selected microRNAs. A logistic regression model was constructed using a training cohort (n=357) and then validated using a cohort(n=241). The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. Results: , We identified 8 miRNAs(hsa-miR-206, hsa-miR-141-3p, hsa-miR-433-3p, hsa-miR-1228-5p, hsa-miR-199a-5p, hsa-miR-122-5p, hsa-miR-192-5p and hsa-miR-26a-5p.) formed a miRNA panel that provided a high diagnostic accuracy of HCC (AUC=0.887 and 0.879 for training and validation data set, respectively). The microRNA panel can also differentiate HCC from healthy (AUC =0.894) and cirrhosis (AUC = 0.892), respectively. Conclusions:We found a serum microRNAs panel that has considerable clinical value in diagnosing HCC. 9 serum samples pooled from 3 healthy control donors and 3 HCC patients, 3 cirrhosi patients treated at The First Affiliated Hospital of Soochow University were subjected to Illumina HiSeq 2000 deep sequencing to identify the miRNAs that were significantly differentially expressed.
2015-12-20 | E-GEOD-59418 | biostudies-arrayexpress
Project description:Background: The identification of new high sensitivity and specificity markers for HCC are essential. We aimed to identify serum microRNAs for diagnosing hepatitis B virus (HBV) –related HCC. Methods: Serum microRNA expression was investigated with four cohorts including 667 participants (261 HCC patients ,233 cirrhosi patients and 173 healthy controls), recruited between August 2010 and June 2013. First, An initial screening of miRNA expression by Illumina sequencing was performed using serum samples pooled from HCC patients and controls,respectively. Quantitative reverse-transcriptase polymerase chain reaction assay was then applied to evaluate the expression of selected microRNAs. A logistic regression model was constructed using a training cohort (n=357) and then validated using a cohort(n=241). The area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. Results: , We identified 8 miRNAs(hsa-miR-206, hsa-miR-141-3p, hsa-miR-433-3p, hsa-miR-1228-5p, hsa-miR-199a-5p, hsa-miR-122-5p, hsa-miR-192-5p and hsa-miR-26a-5p.) formed a miRNA panel that provided a high diagnostic accuracy of HCC (AUC=0.887 and 0.879 for training and validation data set, respectively). The microRNA panel can also differentiate HCC from healthy (AUC =0.894) and cirrhosis (AUC = 0.892), respectively. Conclusions:We found a serum microRNAs panel that has considerable clinical value in diagnosing HCC.
2015-12-20 | GSE59418 | GEO
Project description:The lack of biomarkers for patient stratification, taking into consideration tumor heterogeneity and innate drug resistance, represents a major issue for the management of hepatocellular carcinoma (HCC) patients, leading to treatment failure in a high percentage of cases. Moreover, the discovery of biomarkers is a clinical challenge for monitoring disease progression in patients undergoing targeted therapies. This study aimed to investigate the microRNA profile in rat HCC specimens compared to normal rat liver.
2019-09-30 | E-MTAB-7624 | biostudies-arrayexpress
Project description:There is an urgent need for developing more effective therapies for aggressive hepatocellular carcinoma (HCC). Guadecitabine (SGI-110) is a second-generation DNA methyltransferase inhibitor (DNMTi) currently in clinical trials for HCC and shows greater stability and performance over first generation DNMTis. The aim of this study is to identify potential therapeutic targets of SGI-110 for clinical trials.
2018-06-26 | GSE105065 | GEO
Project description:Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the major primary liver cancers in adults. It has been shown the phenotypic overlap between HCC and CC, comprising continuous liver cancer spectrum. As a proof of concept, a recent study has demonstrated a genomic subtype of HCC expressing CC-like gene expression trait, i.e. CC-like HCC, which has revealed common genomic trait of stem cell-like property and aggressive clinical outcome. However, the histopathological characteristics of these intermediate phenotype was not fully evaluated yet. Here, we found that a variant HCC with fibrous stromal component, i.e. scirrhous HCC, has CC-like genomic features. By performing gene expression profiling and immunohistochemical evaluation, we compared the morphological and molecular features of scirrhous HCC with CC and classical HCC. We found that the scirrhous HCC express both CC-like and stem cell-like expression traits. In addition, we observed the expression of core epithelial-mesenchymal transition (EMT)-related genes, which may contribute to the aggressive behavior of scirrhous HCC. Over-expression of transforming growth factor β (TGF-β) signaling was also found, implying its regulatory role in the pathobiology of scirrhous HCC. Conclusion: We suggest that the fibrous stromal component in HCC may contribute to the acquisition of CC-like gene expression trait in HCC. The expression of stem cell-like trait and TGF-β/EMT molecules may play pivotal roles in the aggressive phenotype of scirrhous HCC Gene expression profiles of HCC, CC and HCC with fibrous stroma were compared.
2012-08-31 | E-GEOD-31370 | biostudies-arrayexpress
Project description:The clinical outcomes of hepatocellular carcinoma (HCC) remain dismal. Elucidating the molecular mechanisms for the progression of aggressive HCC holds the promise for developing novel intervention strategies. The transactivation response element RNA-binding protein (TRBP/TARBP2), a key component of microRNA (miRNA) processing and maturation machinery has exhibited to play conflicting roles in tumor development and progression. We sought to investigate the expression of TARBP2 in HCC using well-characterized HCC cell lines, patient-derived tissues and blood samples. Additionally, the potential prognostic and diagnostic value of TARBP2 in HCC were analyzed using Kaplan-Meier plots and ROC curve. Cell counting kit‐8 (CCK‐8), wound healing and transwell assays examined the ability of TARBP2 to induce cell proliferation, migration, and invasion in HCC cell lines. RNA sequencing was applied to identify the downstream elements of TARBP2. The interaction of potential targets of TARBP2, miR‐145 and serpin family E member 1 (SERPINE1), was assessed using luciferase reporter assay. TARBP2 expression was down-regulated in HCC cell lines relative to normal hepatocyte cells, with a similar pattern further confirmed in tissue and blood samples. Notably, the loss of TARBP2 was demonstrated to promote proliferation, migration, and invasion in HCC cell lines. Interestingly, the reduction of TARBP2 was shown to result in the upregulation of SERPINE1, also known as plasminogen activator inhibitor (PAI-1), which is a vital gene of the HIF-1 signaling pathway. Knockdown of SERPINE1 rescued the TARBP2-lost phenotype. Moreover, TARBP2 depletion induced the upregulation of SERPINE1 through reducing the processing of miR-145, which directly targets SERPINE1. Finally, overexpression of miR-145 repressed SERPINE1 and rescued the functions in sh-TARBP2 HCC cells. Our findings underscore a linear TARBP2-miR-145-SERPINE1 pathway that drives HCC progression, with the potential as a novel intervention target for aggressive HCC.
2021-05-26 | GSE143551 | GEO
Project description:Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor due to activation of multiple cellular pathways and molecular alterations. Herein, we report the first molecular classification of 89 HCC based on the expression of 358 microRNAs and integrative genomic analysis. Three main subclasses of HCC were identified : two of them were associated with beta-catenin mutations or aggressive phenotype. A subset of the subclass of aggressive tumors (8/89, 9%) showed overexpression of a cluster of microRNAs located on chr19q13.41 (C19MC locus. We showed that miR 517a, representing C19MC, promoted cell proliferation, migration and invasion in vitro and induced the development of aggressive tumors in vivo suggesting its role as a novel oncogenic driver in HCC. This SuperSeries is composed of the SubSeries listed below.
2011-02-17 | GSE20596 | GEO
Project description:To identify therapeutic targets with high specificity to HCC, we searched for genes significantly up-regulated in HCC over corresponding non-tumor liver using high-density microarrays Keywords: disease state analysis
2010-06-15 | GSE12941 | GEO