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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 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE31370 | GEO | 2012/08/31

SECONDARY ACCESSION(S): PRJNA145895

REPOSITORIES: GEO

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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 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.

2012-08-31 | E-GEOD-31370 | biostudies-arrayexpress

Genome-wide identification of transcripts associated with lncRNA-ATB by RIP-seq

Project description:The role of TGF-β-induced epithelial-mesenchymal transition (EMT) in cancer cell dissemination is well established, but the involvement of lncRNAs in TGF-β signaling is still unknown. In this study, we observed that the lncRNA-Activated by TGF-β (lncRNA-ATB) was upregulated in hepatocellular carcinoma (HCC) metastases and associated with poor prognosis. lncRNA-ATB upregulated ZEB1 and ZEB2 by competitively binding the miR-200 family and then induced EMT and invasion. In addition, lncRNA-ATB promoted organ colonization of disseminated tumor cells by binding IL11 mRNA, inducing autocrine of IL11 and triggering STAT3 signaling. Globally, lncRNA-ATB promotes the invasion-metastasis cascade. Thus, these findings suggest that lncRNA-ATB, a mediator of TGF-β signaling, could predispose HCC patients to metastases and may serve as a potential target for anti-metastatic therapies. To identify mRNA species bound by lncRNA-ATB, we performed an RIP to pull down endogenous mRNAs associated with the lncRNA-ATB and sequenced the retrieved RNA.

2014-02-08 | E-GEOD-54799 | 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

Long non-coding RNAs and mRNAs regulated by TGF-β

2014-02-08 | GSE54797 | GEO

Genome-wide identification of transcripts associated with lncRNA-ATB by RIP-seq

2014-02-08 | GSE54799 | GEO

TGF-β promotes genomic instability after loss of RUNX3

Project description:Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based in the tumor microenvironment (TME). TGF-β is the most abundantly secreted cytokine in the TME where it imparts various aggressive characteristics including invasive migration, drug resistance and epithelial-to-mesenchymal transition (EMT). Here we show that TGF-β also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells which lack the tumor suppressor gene RUNX3. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP). Recapitulating the above findings, tumors harbouring a TGF-β gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGF-β-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell-extrinsic TGF-β signaling and cancer cell-intrinsic RUNX3 inactivation as aggravating factors for genomic instability.

2019-06-20 | GSE133037 | GEO

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

2012-04-01 | GSE35306 | GEO

Gene expression in epithelial, EMT (epithelial-mesenchymal transition) and MET (mesenchymal-epithelial transition) cells

Project description:NMuMG is an epithelial cell line that can be induced into EMT by TGF-β treatment or MET by TGF-β withdrawl. During EMT, several marker genes were downregulated/upregulated, which is consistent with its mesenchymal phenotype. Transcription factors that are regulated during EMT and its reverse process MET are candidate genes for the regulations of the EMT marker genes. NMuMG cells treated with vehicle, TGF-β for 11 days, or 11days of TGF-β treatment followed by TGF-β withdrawl for another 13 days. RNA from these 3 conditions of NMuMG were extracted and subject to microarray analysis

2013-07-26 | E-GEOD-48204 | biostudies-arrayexpress

Growth Differentiation Factor 1-Induced Tumour Plasticity Provides A Therapeutic Window for Immunotherapy in Hepatocellular Carcinoma

Project description:Poorly differentiated hepatocellular carcinoma (HCC) is an aggressive disease with poor prognosis. Here the authors show that GDF1, a member of the TGF-β superfamily, is highly expressed in high-grade poorly differentiated HCC and is associated with tumor plasticity, and that GDF1-induced re-expression of cancer testis antigens could render tumors sensitive to immune checkpoint inhibition.

2021-11-17 | GSE188582 | 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-β 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-β signaling. Our data confirmed Smad7 as a functional target through which TGF-β-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-β-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-β -induced EMT36.

2013-12-01 | GSE52077 | GEO

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