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Oncogenic ?-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice.

ABSTRACT: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Its pathogenesis is frequently linked to liver inflammation. Gain-of-function mutations in the gene encoding ?-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of ?-catenin-induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic ?-catenin signaling was found to induce an inflammatory program in hepatocytes that involved direct transcriptional control by ?-catenin and activation of the NF-?B pathway. This led to a specific inflammatory response, the intensity of which determined the degree of tumor aggressiveness. The chemokine-like chemotactic factor leukocyte cell-derived chemotaxin 2 (LECT2) and invariant NKT (iNKT) cells were identified as key interconnected effectors of liver ?-catenin-induced inflammation. In genetic deletion models lacking the gene encoding LECT2 or iNKT cells, hepatic ?-catenin signaling triggered the formation of highly malignant HCCs with lung metastasis. Thus, our results identify inflammation as a key player in ?-catenin-induced liver tumorigenesis. We provide strong evidence that, by activating pro- and antiinflammatory mediators, ?-catenin signaling produces an inflammatory microenvironment that has an impact on tumoral development. Our data are consistent with the fact that most ?-catenin-activated HCCs are of better prognosis.

SUBMITTER: Anson M

PROVIDER: S-EPMC3266772 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice.

Anson Marie M Crain-Denoyelle Anne-Marie AM Baud Véronique V Chereau Fanny F Gougelet Angélique A Terris Benoit B Yamagoe Satoshi S Colnot Sabine S Viguier Mireille M Perret Christine C Couty Jean-Pierre JP

The Journal of clinical investigation 20120117 2

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Its pathogenesis is frequently linked to liver inflammation. Gain-of-function mutations in the gene encoding β-catenin are frequent genetic modifications found in human HCCs. Thus, we investigated whether inflammation was a component of β-catenin-induced tumorigenesis using genetically modified mouse models that recapitulated the stages of initiation and progression of this tumoral process. Oncogenic β-c ...[more]

PMID: 22251704

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Project description:Recently, we have shown that coexpression of hMet and mutant-β-catenin using sleeping beauty transposon/transposase leads to hepatocellular carcinoma (HCC) in mice that corresponds to around 10% of human HCC. In the current study, we investigate whether Ras activation, which can occur downstream of Met signaling, is sufficient to cause HCC in association with mutant-β-catenin. We also tested therapeutic efficacy of targeting β-catenin in an HCC model. We show that mutant-K-Ras (G12D), which leads to Ras activation, cooperates with β-catenin mutants (S33Y, S45Y) to yield HCC in mice. Affymetrix microarray showed > 90% similarity in gene expression in mutant-K-Ras-β-catenin and Met-β-catenin HCC. K-Ras-β-catenin tumors showed up-regulation of β-catenin targets like glutamine synthetase (GS), leukocyte cell-derived chemotaxin 2, Regucalcin, and Cyclin-D1 and of K-Ras effectors, including phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phosphorylated mammalian target of rapamycin, phosphorylated eukaryotic translation initiation factor 4E, phosphorylated 4E-binding protein 1, and p-S6 ribosomal protein. Inclusion of dominant-negative transcription factor 4 at the time of K-Ras-β-catenin injection prevented HCC and downstream β-catenin and Ras signaling. To address whether targeting β-catenin has any benefit postestablishment of HCC, we administered K-Ras-β-catenin mice with EnCore lipid nanoparticles (LNP) loaded with a Dicer substrate small interfering RNA targeting catenin beta 1 (CTNNB1; CTNNB1-LNP), scrambled sequence (Scr-LNP), or phosphate-buffered saline for multiple cycles. A significant decrease in tumor burden was evident in the CTNNB1-LNP group versus all controls, which was associated with dramatic decreases in β-catenin targets and some K-Ras effectors, leading to reduced tumor cell proliferation and viability. Intriguingly, in relatively few mice, non-GS-positive tumors, which were evident as a small subset of overall tumor burden, were not affected by β-catenin suppression.ConclusionRas activation downstream of c-Met is sufficient to induce clinically relevant HCC in cooperation with mutant β-catenin. β-catenin suppression by a clinically relevant modality is effective in treatment of β-catenin-positive, GS-positive HCCs. (Hepatology 2017;65:1581-1599).

Dataset Information

Oncogenic ?-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice.

Publications

Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice.

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