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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Fibrous stromal component in hepatocellular carcinoma reveals a cholangiocarcinoma-like gene expression trait and epithelial-mesenchymal transition.

ABSTRACT: 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 Î² (TGF-Î²) 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-Î²/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.

ORGANISM(S): Homo sapiens

SUBMITTER: Hyun Goo Woo

PROVIDER: E-GEOD-31370 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Fibrous stromal component in hepatocellular carcinoma reveals a cholangiocarcinoma-like gene expression trait and epithelial-mesenchymal transition.

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

2012-08-31 | GSE31370 | GEO

Identification of miR-181a target genes in Epithelial Ovarian Cancer

Project description:We have identified a single miRNA, miR-181a, that can modulate TGF-Î² signaling to induce and maintain EMT, and effect further downstream events of tumour cell survival, altered response to chemotherapy, migration, invasion and dissemination in vivo. Our present study provides an understanding of how enhanced expression of miR-181a can confer malignant and invasive traits through the modulation of a canonical signaling pathway and a consequent maintenance of a mesenchymal state. Furthermore, inhibition of miR-181a led to a reversion of EMT and subsequent events through decreased TGF-Î² signaling. Our data confirmed Smad7 as a functional target through which TGF-Î²-mediated EMT occurs; re-expression of Smad7 lacking its 3'UTR was able to rescue miR-181a-mediated phenotypes, deeming Smad7 as a critical mediator of miR-181a-induced EMT. Other recent studies support the crucial role(s) that miRNAs play in mediating EMT and consequent aggressive disease traits. For example, the miR-106b-25 cluster has also been shown to target Smad7 and mediate TGF-Î²-induced EMT downstream to Six1 in breast cancer34. miR-9 directly targets E-cadherin and inhibition of miR-9 had led to an inhibition of metastasis35. Conversely, the miR-200 and -205 family was shown to target transcriptional repressors of E-cadherin, ZEB1 and SIP1, and re-expression of these miRNAs led to a mesenchymal-to-epithelial transition and prevented TGF-Î² -induced EMT36. A2780 ovarian cancer cell lines stably expressing either pBABE (control vector), p181a#1( clone 1 expressing miR-181a) or p181a#2( clone 2 expressing miR-181a)

2013-12-01 | E-GEOD-52077 | biostudies-arrayexpress

Overexpression of PHF8 promotes an EMT-related gene signature in MCF10A cells

Project description:PHF8 exerts distinct functions in different types of cancer. However, the mechanisms underlying its specific functions in each case remain obscure. To establish whether overexpression of PHF8 regulates the TGF-Î² induced the epithelial-mesenchymal transition (EMT), we treated MCF10A-Mock (control) and MCF10A-PHF8wt (overexpressing wild-type PHF8) cells with TGF-Î²1 for 0, 24, 48 and 72 hours and performed RNA-seq in biological duplicates. Our data indicated that EMT gene signatures were significantly enriched in MCF10A-PHF8 cells with TGF-Î²1 treatment at all time points, strongly indicating that PHF8 overexpression induces a sustained EMT signaling program. mRNA profiles of MCF10A-Mock (control) and MCF10A-PHF8 with TGF-Î²1 treatment for 0, 24, 48 and 72 hours were generated by RNA-seq, in duplicate, using HiSeq2500 instrument.

2016-10-26 | E-GEOD-74377 | biostudies-arrayexpress

Vicious circle of LSD1 and TGF Î²1 promotes EMT of gastric cancer

Project description:Vicious circle of some key proteins is critical in the process of tumor development. Nevertheless, the mechanism of how the epigenetic modifiers are involved in was seldom reported and has not been clearly illustrated. We found the expression of lysine specific demethylase 1 (LSD1), the first identified histone lysine demethylase, is positively correlated with transforming growth factor beta 1 (TGF Î²1) in gastric cancer tissues and can be promoted by TGF Î²1 activated (p-EKR)-(NF-ÎºB)-p300 signaling pathway, which resulted in the progression of epithelial-mesenchymal transition (EMT) in human gastric cancer cells. On the other hand, abrogation of LSD1 leads to the down regulation of TGF Î²1 as well as the EMT. But in benign cells, this circle was blocked by TGF Î²1 induced inactivation of ERK, which suggested the distinct roles of TGF Î²1 against LSD1 in gastric cancer cells and benign cells. This vicious cycle may illustrate a novel mechanism for EMT in gastric cancer mediate by TGF Î²1 and LSD1 but not in benign cells and may serve as a new strategy for the prevention of EMT for gastric cancer. Nuclear extracts prepared from MGC803 cells stably expressing Lenti-CAS9-sgRNA-puro for LSD1 or empty vector were used in immunoprecipitation reactions with antibodies against H3K4me2 and H3K9me2. Sequencing libraries were prepared using the TruSeq DNA Sample Prep Kit (Illumina) and sequencing was performed on a HiSeq2000 (Illumina).

2016-07-19 | E-GEOD-84487 | biostudies-arrayexpress

Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFbeta signaling pathways

Project description:Primary liver tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and a group of rare tumours exhibiting biliary and hepatocytic differentiation called combined hepatocholangiocarcinomas (cHCC-CC). To better define this latter group, we take advantage of a series of these tumours based on their morphological characteristics and we performed transcriptional analysis allowing thereafter global comparison with published data. We show that most cHCC-CCs express progenitor cell traits, are committed to biliary lineage and are mainly associated to the activation of Wnt/beta-catenin and TGFbeta signalling pathways. Wnt/beta-catenin pathway activation in cHCC-CC is evidenced by the expression of both its direct targets such as LEF1 and EPCAM. In addition, extracellular matrix (ECM) genes and ECM-remodelling genes which are upon the control of TGF profibrotic program were found up-regulated in cHCC-CC. Interestingly, we show that CC and most cHCC-CC share characteristics associated to a subtype of poorly differentiated HCC suggesting that these tumours could originate from a stem/progenitor cell. The plasticity of these cells may explain the phenotypical heterogeneity of these tumors with the maintenance of some hepatocellular differentiation features such as albumin expression. Interestingly, this is shared by at least one third of CC, raising the hypothesis of a potential continuum between CC, cHCC-CC and poorly differentiated HCC. Patients serie include 3 intra-hepatic CC, 7 typical HCC and 20 cHCC-CC that was used for microarray hybridisation. All these tumours did not show any mutation of the beta-catenin gene. The degree of hepatic fibrosis of the non-cancerous liver was graded according to the METAVIR classification. Paraffin sections were processed as described previously. Immunohistochemistry was done on standard slides for the series.

2012-03-31 | E-GEOD-35306 | biostudies-arrayexpress

Identification of cholangiocarcinoma-like gene expression traits in hepatocellular carcinoma

Project description:We performed gene expression profiling of hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and mixed type of combined HCC and CC (CHC). In comparison of the profiles, a novel class of HCC expressing CC-like traits was identified. Gene expression profiling of 70 hepatocellular carcinoma (HCC), 13 cholangiocarcinoma (CC), and 7 mixed type of combined HCC and CC (CHC) were performed.

2010-06-09 | E-GEOD-15765 | biostudies-arrayexpress

TGF-Î² Tumor Suppression Through A Lethal EMT

Project description:TGF-Î² is a major tumor suppressor in gastrointestinal (GI) and squamous carcinomas, which exhibit frequent genetic inactivation of Smad4, a key TGF-Î² signaling component. Apoptosis is implicated as an important mediator of the tumor suppressive function of TGF-Î², although this process remains poorly understood. To address this long-standing question, we dissected the tumor suppressive action of TGF-Î² in naÃ¯ve pancreatic ductal adenocarcinoma (PDA) cells. Here we show that TGF-Î²/Smad4 signaling triggers an EMT in Kras-mutant pancreatic progenitor cells but turns this process into a trigger of apoptosis by converting the progenitor cell transcription factor Sox4 from an enforcer of epithelial progenitor identity into an activator of apoptosis. This occurs as a result of the EMT-linked repression of the endodermal master regulator Klf5, which cooperates with Sox4 to promote epithelial progenitor identity, and loss of which unmasks a latent apoptotic transcriptional program driven by Sox4. By losing Smad4, Kras-mutant PDA cells avoid this fate and instead use Sox4 as a TGF-Î²-dependent enforcer of the epithelial progenitor cell state. In this study, 16 RNA-Seq samples and 6 ChIP-Seq samples are included.

2016-02-24 | E-GEOD-72069 | biostudies-arrayexpress

Combined hepatocellular-cholangiocarcinomas exhibit progenitor features and activation of Wnt and TGFbeta signaling pathways

2012-04-01 | GSE35306 | GEO

Expression data for human nasopharyngeal carcinoma cell line HK1 stimulated with EGF or TGF-Î² recombinant protein.

Project description:As regulators in gene expression, microRNAs take part in most biological process including cell differentiation, apoptosis, cell cycle and epithelial-to-mesenchymal transition (EMT). In order to evaluate their roles during the growth factors-induced EMT process, microRNA expression profile changes induced by EGF or TGF-Î² treatment on nasopharyngeal carcinoma cell line HK-1 cells were analyzed by means of the Affymetrix genome wide microarray system. Human nasopharyngeal carcinoma cell line HK-1 was starved for 12 hours before stimulation with EGF (50 ng/mL) or TGF-Î² (10ng/ml) or Control (PBS) for 36 hours in RPMI-1640 medium (with 1% serum) to establish the in vitro model of EMT. Total RNA were extracted and detected by AffymetrixÂ® GeneChipÂ® miRNA Arrays.

2015-12-17 | E-GEOD-64281 | biostudies-arrayexpress

Identification of cholangiocarcinoma-like gene expression traits in hepatocellular carcinoma

2010-05-21 | GSE15765 | GEO

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