Transcriptomic and epigenetic signatures of hepatocellular carcinoma and intrahepatic cholangiocarcinoma derived from oncogenically transformed murine hepatocytes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE112617 | GEO | 2018/06/29
REPOSITORIES: GEO
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Project description:Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and therapy response. Yet, molecular actors and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here, we report that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumourigenesis. While a necroptosis associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes harbouring identical oncogenic drivers give rise to HCC if surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of murine HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage commitment factors, a function conserved in humans. Together, our study provides unprecedented insights into lineage commitment in liver tumourigenesis and explains molecularly why common liver damaging risk factors can either lead to HCC or ICC.
2018-06-28 | GSE112615 | GEO
Project description:Transcriptomic and epigenetic signatures of hepatocellular carcinoma and intrahepatic cholangiocarcinoma derived from oncogenically transformed murine hepatocytes
| PRJNA448523 | ENA
Project description:Primary liver cancer represents a major health problem. It comprises hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), which differ markedly with regards to their morphology, metastatic potential and therapy response. Yet, molecular actors and tissue context that commit transformed hepatic cells towards HCC or ICC are largely unknown. Here, we report that the hepatic microenvironment epigenetically shapes lineage commitment in mosaic mouse models of liver tumourigenesis. While a necroptosis associated hepatic cytokine microenvironment determines ICC outgrowth from oncogenically transformed hepatocytes, hepatocytes harbouring identical oncogenic drivers give rise to HCC if surrounded by apoptotic hepatocytes. Epigenome and transcriptome profiling of murine HCC and ICC singled out Tbx3 and Prdm5 as major microenvironment-dependent and epigenetically regulated lineage commitment factors, a function conserved in humans. Together, our study provides unprecedented insights into lineage commitment in liver tumourigenesis and explains molecularly why common liver damaging risk factors can either lead to HCC or ICC.
2018-06-29 | GSE112616 | GEO
Project description:Transcriptomic signature of hepatocellular carcinoma and intrahepatic cholangiocarcinoma derived from oncogenically transformed murine hepatocytes
| PRJNA448524 | ENA
Project description:The role of external beam radiation therapy for primary liver malignancies has historically been limited due to the risk of radiation-induced liver disease. However, with the advent of stereotactic body radiotherapy (SBRT), we are able to dose escalate while safely sparing critical nearby structures. This review explores the evidence surrounding the use of SBRT for the treatment of primary liver malignancies. A review of the literature was performed. This article discusses the challenges, efficacy, and safety of SBRT for primary liver malignancies in order to conceptualize its role within a multidisciplinary framework. Prospective phase I and II trials show local control rates at 1 to 2 years ranging from 65% to 100%. Overall survival at 1 to 2 years ranged from 48% to 77%. Grade >3 toxicity ranged from 0% to 36%. Total radiotherapy doses ranged from 24 to 60 Gy delivered in 1 to 6 fractions. The SBRT offers a noninvasive therapy for patients with limited treatment options and should be considered in a multidisciplinary setting for the management of unresectable, locally advanced primary liver malignancies. Prospective randomized trials are warranted to determine the efficacy and safety of SBRT compared to and in combination with other treatment modalities.
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Project description:In this study,we performed integrated glycoproteomic and global proteomic analysis of tumor tissues of ICC and HCC to investigate the differences in site-specific glycosylation and proteins between ICC and HCC tumors. The paired paracancer tissue were also included as controls to determine the site-specific glycosylation changes in ICC and HCC tumors. The alteration extents in glycopeptide, global proteome, and normalized glycosylation in different sample groups were systematically compared.
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Project description:We performed genomic and transcriptomic sequencing of 133 combined hepatocellular and intrahepatic cholangiocarcinoma (cHCC-ICC) cases, including separate, combined, and mixed subtypes. Integrative comparison of cHCC-ICC with hepatocellular carcinoma and intrahepatic cholangiocarcinoma revealed that combined and mixed type cHCC-ICCs are distinct subtypes with different clinical and molecular features. Integrating laser microdissection, cancer cell fraction analysis, and single nucleus sequencing, we revealed both mono- and multiclonal origins in the separate type cHCC-ICCs, whereas combined and mixed type cHCC-ICCs were all monoclonal origin. Notably, cHCC-ICCs showed significantly higher expression of Nestin, suggesting Nestin may serve as a biomarker for diagnosing cHCC-ICC. Our results provide important biological and clinical insights into cHCC-ICC.
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Project description:Hepatocellular carcinoma (HCC) is a primary malignancy with increasing incidence and poor prognosis. Heterogeneity originating from genomic instability is one of the critical reasons of poor outcomes. However, the studies of underlying mechanisms and pathways affected by mutations are still not intelligible. Currently, integrative molecular-level studies using multiomics approaches enable comprehensive analysis for cancers, which is pivotal for personalized therapy and mortality reduction. In this study, genomic and transcriptomic data of HCC are obtained from The Cancer Genome Atlas (TCGA) to investigate the affected coding and non-coding RNAs, as well as their regulatory network due to certain mutational signatures of HCC. Different types of RNAs have their specific enriched biological functions in mutational signature-specific HCCs, upregulated coding RNAs are predominantly associated with lipid metabolism-related pathways, and downregulated coding RNAs are enriched in axonogenesis for tumor microenvironment generation. Additionally, differentially expressed miRNAs are inclined to concentrate in cancer-related signaling pathways. Some of these RNAs also serve as prognostic factors that help predict the survival outcome of HCCs with certain mutational signatures. Furthermore, deregulation of competing endogenous RNA (ceRNA) regulatory network is identified, which suggests a potential therapy via interference of miRNA activity for mutational signature-specific HCC. This study proposes a projection approach to reduce therapeutic complexity from genomic mutations to transcriptomic alterations. Through this method, we identify genes and pathways critical for mutational signature-specific HCC and further discover a series of prognostic markers indicating patient survival outcome.
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Project description:The present study aimed to explore the value of intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) in differentiating hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC). This study included 65 patients with malignant hepatic nodules (55 with HCC, 10 with ICC), and 17 control patients with normal livers. All patients underwent IVIM-DWI scans on a 3.0?T magnetic resonance imaging (MRI) scanner. The standard apparent diffusion coefficient (ADC), pure diffusion coefficient (Dslow), pseudo-diffusion coefficient (Dfast), and perfusion fraction (f) were obtained. Differences in the parameters among the groups were analysed using one-way ANOVA, with p?<?0.05 indicating statistical significance. Receiver operating characteristic (ROC) curve analysis was used to compare the efficacy of each parameter in differentiating HCC from ICC. ADC, Dslow, Dfast, f significantly differed among the three groups. ADC and Dslow were significantly lower in the HCC group than in the ICC group, while Dfast was significantly higher in the HCC group than in the ICC group; f did not significantly differ between the HCC and ICC groups. When the cut-off values of ADC, Dslow, and Dfast were 1.27 × 10-3 mm2/s, 0.81 × 10-3 mm2/s, and 26.04 × 10-3 mm2/s, respectively, their diagnostic sensitivities for differentiating HCC from ICC were 98.18%, 58.18%, and 94.55%, their diagnostic specificities were 50.00%, 80.00%, and 80.00%, and their areas under the ROC curve (AUCs) were 0.687, 0.721, and 0.896, respectively. Dfast displayed the largest AUC value. IVIM-DWI can be used to differentiate HCC from ICC.
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Project description:Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are liver originated malignant tumors. Of the two, ICC has the worse prognosis because it has no reliable diagnostic markers and its carcinogenic mechanism is not fully understood. The aim of this study was to integrate metabolomics and transcriptomics datasets to identify variances if any in the carcinogenic mechanism of ICC and HCC. Ten ICC and 6 HCC who were resected surgically, were enrolled. miRNA and mRNA expression analysis were performed by microarray on ICC and HCC and their corresponding non-tumor tissues (ICC_NT and HCC_NT). Compound analysis was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Principle component analysis (PCA) revealed that among the four sample groups (ICC, ICC_NT, HCC, and HCC_NT) there were 14 compounds, 62 mRNAs and 17 miRNAs with two distinct patterns: tumor and non-tumor, and ICC and non-ICC. We accurately (84.38%) distinguished ICC by the distinct pattern of its compounds. Pathway analysis using transcriptome and metabolome showed that several pathways varied between tumor and non-tumor samples. Based on the results of the PCA, we believe that ICC and HCC have different carcinogenic mechanism therefore knowing the specific profile of genes and compounds can be useful in diagnosing ICC.
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