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| Status |
Public on Jul 05, 2022 |
| Title |
An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents II |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Background & Aims: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
To assess the impact of sulindac or aspirin/clopidogrel treatment on the immune-mediated cancer field, we collected samples from a choline-deficient high-fat diet fed mouse model developing NASH, HCC and fibrosis, previously published (Malehmir M et al, Nat Med, 2019) . We analyzed gene expression profiling of non-tumor liver samples from mice fed a CD-HFD for 12 weeks treated with vehicle that presented HCC and fibrosis (considered as high-risk group) (n=4); as well as mice fed a CD-HFD for 12 weeks treated with sulindac (n=10) or aspirin/clopidogrel (n=6). As controls, we analyzed samples from mice fed a chow-diet for 12 weeks (considered as healthy group) (n=5).
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| Overall design |
Fresh-frozen liver tissues from 30 mice (5 control, 4 vehicle-treated, 10 sulindac-treated and 6 aspirin/clopidogrel treated), were collected and RNA was extracted. Whole-genome transcriptome analysis was obtained using ene Chip HT MG-430 (Affymetrix) according to manufacturer’s protocols. Raw expression data from microarrays were normalized using the ExpressionFileCreator [RMA with quantile normalization method].
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| Contributor(s) |
Llovet JM, Sia D, Heikenwälder M |
| Citation missing |
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| Submission date |
Jul 08, 2019 |
| Last update date |
Jul 07, 2022 |
| Contact name |
Sara Torrecilla |
| Organization name |
IDIBAPS
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| Lab |
Liver Cancer Translational Research Laboratory
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| Street address |
Rossello Street, 149
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| City |
Barcelona |
| State/province |
Catalonia |
| ZIP/Postal code |
08036 |
| Country |
Spain |
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| Platforms (1) |
| GPL11180 |
[HT_MG-430_PM] Affymetrix HT MG-430 PM Array Plate |
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| Samples (30)
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| Relations |
| BioProject |
PRJNA553221 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE133969_RAW.tar |
65.4 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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