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

Intrahepatic malignant tumours include hepatocellular carcinomas (HCC), cholangiocarcinomas (CC) and combined hepatocholangiocarcinomas (cHCC-CC), a group of rare and poorly characterized tumours that exhibit both biliary and hepatocytic differentiation. The aim of the study was to characterize the molecular pathways specifically associated with cHCC-CC pathogenesis. We performed a genome-wide transcriptional analysis of 20 histologically defined cHCC-CC and compared them with a series of typical HCC and of CC. Data were analysed by gene set enrichment and integrative genomics and results were further validated in situ by tissue microarray using an independent series of 152 tumours. We report that cHCC-CC exhibit stem/progenitor features, a down-regulation of the hepatocyte differentiation program and a commitment to the biliary lineage. TGFβ and Wnt/β-catenin were identified as the two major signalling pathways activated in cHCC-CC. A β-catenin signature distinct from that observed in well-differentiated HCC with mutant β-catenin was found in cHCC-CC. This signature was associated with microenvironment remodelling and TGFβ activation. Furthermore, integrative genomics revealed that cHCC-CC share characteristics of poorly differentiated HCC with stem cell traits and poor prognosis. The common traits displayed by CC, cHCC-CC and some HCC suggest that these tumours could originate from stem/progenitor cell(s) and raised the hypothesis of a potential continuum between intrahepatic CC, cHCC-CC and poorly differentiated HC

The treatment response of chronically hepatitis C virus-infected patients depends on interferon concentration but not on interferon gene expression in peripheral blood mononuclear cells.

International audienceThe current treatment of chronic hepatitis C is based on pegylated alpha interferon (PEG-IFN-α) and ribavirin. The aim of this study was to identify biological and clinical variables related to IFN therapy that could predict patient outcome. The study enrolled 47 patients treated with PEG-IFN and ribavirin combined therapy. The interferon concentration was measured in serum by a bioassay. The expression of 93 interferon-regulated genes in peripheral blood mononuclear cells was quantified by real-time quantitative reverse transcription-PCR (RT-PCR) before and after 1 month of treatment. The interferon concentration in the serum was significantly lower in nonresponders than in sustained virological responders. Moreover, a significant correlation was identified between interferon concentration and interferon exposition as well as body weight. The analysis of interferon-inducible genes in peripheral blood mononuclear cells among the genes tested did not permit the prediction of treatment outcome. In conclusion, the better option seems to be to treat patients with weight-adjusted PEG-IFN doses, particularly for patients with high weight who are treated with PEG-IFN-α2a. Although the peripheral blood mononuclear cell samples are the easiest to obtain, the measurement of interferon-inducible genes seems not be the best strategy to predict treatment outcome

Regulation of hepatic cardiolipin metabolism by TNFα: Implication in cancer cachexia

International audienceCardiolipin (CL) content accumulation leads to an increase in energy wasting in liver mitochondria in a rat model of cancer cachexia in which tumor necrosis factor alpha (TNFα) is highly expressed. In this study we investigated the mechanisms involved in liver mitochondria CL accumulation in cancer cachexia and examined if TNFα was involved in this process leading to mitochondrial bioenergetics alterations. We studied gene, protein expression and activity of the main enzymes involved in CL metabolism in liver mitochondria from a rat model of cancer cachexia and in HepaRG hepatocyte-like cells exposed to 20 ng/ml of TNFα for 12 h. Phosphatidylglycerolphosphate synthase (PGPS) gene expression was increased 2.3-fold (p < 0.02) and cardiolipin synthase (CLS) activity decreased 44% (p < 0.03) in cachectic rat livers compared to controls. CL remodeling enzymes monolysocardiolipin acyltransferase (MLCL AT-1) activity and tafazzin (TAZ) gene expression were increased 30% (p < 0.01) and 50% (p < 0.02), respectively, in cachectic rat livers compared to controls. Incubation of hepatocytes with TNFα increased CL content 15% (p < 0.05), mitochondrial oxygen consumption 33% (p < 0.05), PGPS gene expression 44% (p < 0.05) and MLCL AT-1 activity 20% (p < 0.05) compared to controls. These above findings strongly suggest that in cancer cachexia, TNFα induces a higher energy wasting in liver mitochondria by increasing CL content via upregulation of PGPS expression

TGF-β1 and TGF-β2 abundance in liver diseases of mice and men

TGF-β1 is a major player in chronic liver diseases promoting fibrogenesis and tumorigenesis through various mechanisms. The expression and function of TGF-β2 have not been investigated thoroughly in liver disease to date. In this paper, we provide evidence that TGF-β2 expression correlates with fibrogenesis and liver cancer development. Using quantitative realtime PCR and ELISA, we show that TGF-β2 mRNA expression and secretion increased in murine HSCs and hepatocytes over time in culture and were found in the human-derived HSC cell line LX-2. TGF-β2 stimulation of the LX-2 cells led to upregulation of the TGF-β receptors 1, 2, and 3, whereas TGF-β1 treatment did not alter or decrease their expression. In liver regeneration and fibrosis upon CCl4 challenge, the transient increase of TGF-β2 expression was accompanied by TGF-β1 and collagen expression. In bile duct ligation-induced fibrosis, TGF-β2 upregulation correlated with fibrotic markers and was more prominent than TGF-β1 expression. Accordingly, MDR2-KO mice showed significant TGF-β2 upregulation within 3 to 15 months but minor TGF-β1 expression changes. In 5 of 8 hepatocellular carcinoma (HCC)/hepatoblastoma cell lines, relatively high TGF-β2 expression and secretion were observed, with some cell lines even secreting more TGF-β2 than TGF-β1. TGF-β2 was also upregulated in tumors of TGFα/cMyc and DEN-treated mice. The analysis of publically available microarray data of 13 human HCC collectives revealed considerable upregulation of TGF-β2 as compared to normal liver. Our study demonstrates upregulation of TGF-β2 in liver disease and suggests TGF-β2 as a promising therapeutic target for tackling fibrosis and HCC

Evaluation of TGFβ, XPO4, elF5A2 and ANGPTL4 as biomarkers in HCC

Hepatocellular carcinoma (HCC) is the most common type of liver cancer, and the fourth leading cause of cancer mortality worldwide. It is often diagnosed at an advanced stage, and hence typically has a poor prognosis. A number of distinct molecules have been recently identified as playing a role in the control of cancer progression. However, patients with HCC have a highly variable clinical course, indicating that HCC comprises several biologically distinctive subgroups reflecting a molecular heterogeneity of the tumors. To evaluate potential biomarkers in HCC, we employed multiple methods in this study, including qPCR, immunostaining methods and tissue microarrays (TMAs), as well as histological and pathological analysis, to assess TGF beta, XPO4, elF5A2 and ANGPTL4 in cancerous and paracancerous liver tissues from 280 patients suffering from liver cancer. Our results found that all four indicators were located in the cytoplasm and distributed in cancerous and paracancerous liver tissues. Generally, there were higher levels of these indicators in paracancerous, compared with cancerous, liver tissues. These four indicators were correlated and modulated among each other. In connection with patient clinical and revisit information, statistical analysis determined that TGF beta 1 in paracancerous liver tissue was positively correlated with tumor size. Higher production of TGF beta 1 in paracancerous liver tissue was always associated with bigger liver tumors. XPO4 in cancerous liver tissue and TGF beta 1 in paracancerous liver tissue were positively correlated with tumor differentiation. TGF beta 1, ANGPTL4 and elF5A2 were also positively correlated with the T classification of tumors. Additionally, higher levels of XPO4 in cancerous liver tissue suggested that the patient would have a better prognosis and survival rate. However, higher production of XPO4 in paracancerous liver tissue suggested a worse prognosis. All the results above provide new insights into better understanding biological indicators, such as XPO4, TGF beta 1, ANGPTL4 and elF5A2, in the prediction and evaluation of liver cancer, as well as signaling pathways in the control of liver cancer. XPO4 and TGF beta 1 may serve as useful markers to evaluate the size and prognosis of liver cancer.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000312236400020&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Medicine, Research &amp; ExperimentalSCI(E)6ARTICLE1119-127

Clinical relevance of biomarkers in cholangiocarcinoma: critical revision and future directions

Cholangiocarcinoma (CCA) is a malignant tumour arising from the biliary system. In Europe, this tumour frequently presents as a sporadic cancer in patients without defined risk factors and is usually diagnosed at advanced stages with a consequent poor prognosis. Therefore, the identification of biomarkers represents an utmost need for patients with CCA. Numerous studies proposed a wide spectrum of biomarkers at tissue and molecular levels. With the present paper, a multidisciplinary group of experts within the European Network for the Study of Cholangiocarcinoma discusses the clinical role of tissue biomarkers and provides a selection based on their current relevance and potential applications in the framework of CCA. Recent advances are proposed by dividing biomarkers based on their potential role in diagnosis, prognosis and therapy response. Limitations of current biomarkers are also identified, together with specific promising areas (ie, artificial intelligence, patient-derived organoids, targeted therapy) where research should be focused to develop future biomarkers

Genes Associated with Recurrence of Hepatocellular Carcinoma: Integrated Analysis by Gene Expression and Methylation Profiling

Gene expression is suppressed by DNA methylation. The goal of this study was to identify genes whose CpG site methylation and mRNA expression are associated with recurrence after surgical resection for hepatocellular carcinoma (HCC). Sixty-two HCCs were examined by both whole genome DNA methylation and transcriptome analysis. The Cox model was used to select genes associated with recurrence. A validation was performed in an independent cohort of 66 HCC patients. Among fifty-nine common genes, increased CpG site methylation and decreased mRNA expression were associated with recurrence for 12 genes (Group A), whereas decreased CpG site methylation and increased mRNA expression were associated with recurrence for 25 genes (Group B). The remaining 22 genes were defined as Group C. Complement factor H (CFH) and myosin VIIA and Rab interacting protein (MYRIP) in Group A; proline/serine-rich coiled-coil 1 (PSRC1), meiotic recombination 11 homolog A (MRE11A), and myosin IE (MYO1E) in Group B; and autophagy-related protein LC3 A (MAP1LC3A), and NADH dehydrogenase 1 alpha subcomplex assembly factor 1 (NDUFAF1) in Group C were validated. In conclusion, potential tumor suppressor (CFH, MYRIP) and oncogenes (PSRC1, MRE11A, MYO1E) in HCC are reported. The regulation of individual genes by methylation in hepatocarcinogenesis needs to be validated

Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas

Somatic STAT3 mutations present in a subset of inflammatory hepatocellular adenomas result in the generation of constitutively active STAT3 proteins that homodimerize independently of IL-6 stimulation

MiR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma

10.1371/journal.pone.0086872PLoS ONE91-POLN