An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents

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RECERCAT Home > Universitat de Barcelona > IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer > Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) > View document

To access the full text documents, please follow this link: http://hdl.handle.net/2445/147179

dc.contributor.author	Moeini, Agrin
dc.contributor.author	Torrecilla, Sara
dc.contributor.author	Tovar, Victoria
dc.contributor.author	Montironi, Carla
dc.contributor.author	Andreu Oller, Carmen
dc.contributor.author	Peix, Judit
dc.contributor.author	Higuera, Mónica
dc.contributor.author	Pfister, Dominik
dc.contributor.author	Ramadori, Pierluigi
dc.contributor.author	Pinyol, Roser
dc.contributor.author	Solé, Manel
dc.contributor.author	Heikenwälder, Mathias
dc.contributor.author	Friedman, Scott L.
dc.contributor.author	Sia, Daniela
dc.contributor.author	Llovet i Bayer, Josep Maria
dc.date	2020-01-08T08:37:51Z
dc.date	2020-01-08T08:37:51Z
dc.date	2019-06-22
dc.date	2020-01-08T08:31:27Z
dc.identifier	5763157
dc.identifier	31344396
dc.identifier.uri	http://hdl.handle.net/2445/147179
dc.description	Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis.We analyzed gene expression profiles of non-tumor liver tissues from 392 patients with early-stage HCC (training set, n=167 and validation set, n=225) and liver tissue from patients with cirrhosis without HCC (n=216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of N-nitrosodiethylamine followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then given orally the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, given orally aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet.We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of non-tumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor beta signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% 1.21-4.80). Mice with chemically-induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel downregulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle.We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that associates with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and developed fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis.
dc.format	15 p.
dc.format	application/pdf
dc.language	eng
dc.publisher	Elsevier
dc.relation	Versió postprint del document publicat a: https://doi.org/10.1053/j.gastro.2019.07.028
dc.relation	Gastroenterology, 2019, vol. 157, num. 5, p. 1383-1397.e11
dc.relation	https://doi.org/10.1053/j.gastro.2019.07.028
dc.relation	info:eu-repo/grantAgreement/EC/H2020/667273/EU//HEP-CAR
dc.rights	cc by-nc-nd (c) AGA Institute, 2019
dc.rights	http://creativecommons.org/licenses/by-nc-nd/3.0/es/
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Càncer
dc.subject	Citoquines
dc.subject	Cancer
dc.subject	Cytokines
dc.title	An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents
dc.type	info:eu-repo/semantics/article
dc.type	info:eu-repo/semantics/acceptedVersion

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