“Fibrous nests” in human hepatocellular carcinoma express a Wnt-induced gene signature associated with poor clinical outcome

Désert, Romain; Mebarki, Sihem; Desille, Mireille; Sicard, Marie; Lavergne, Elise; Renaud, Stéphanie; Bergeat, Damien; Sulpice, Laurent; Perret, Christine; Turlin, Bruno; Clément, Bruno; Musso, Orlando

doi:10.1016/j.biocel.2016.08.017

Cited by 34 publications

(40 citation statements)

References 71 publications

(72 reference statements)

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“…These observations are in agreement with the loss of hepatocyte differentiation and the acquisition of invasive properties in hepatic parenchyma deficient for this miRNA . It is notable that the specific microenvironment of the HCC stem cell niche is embodied within the so‐called fibrous nests that share the signaling environment for both the fibrosis and the carcinogenesis. Common features of these hepatic processes include their dependence on the lack of miR‐122, which normally suppresses the Wnt signaling and the remodeling of the laminin‐containing basement membranes .…”

Section: A Tissue‐cooperative Homeostatic Model Of Non‐alcoholic Fattsupporting

confidence: 85%

Adipose may actively delay progression of NAFLD by releasing tumor‐suppressing, anti‐fibrotic miR‐122 into circulation

2018

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Summary Nonalcoholic fatty liver disease (NAFLD) is the most common liver pathology. Here we propose tissue‐cooperative, homeostatic model of NAFLD. During early stages of NAFLD the intrahepatic production of miR‐122 falls, while the secretion of miRNA‐containing exosomes by adipose increases. Bloodstream carries exosome to the liver, where their miRNA cargo is released to regulate their intrahepatic targets. When the deterioration of adipose catches up with the failing hepatic parenchyma, the external supply of liver‐supporting miRNAs gradually tapers off, leading to the fibrotic decompensation of the liver and an increase in hepatic carcinogenesis. This model may explain paradoxical observations of the disease‐associated decrease in intrahepatic production of certain miRNAs with an increase in their levels in serum. Infusions of miR‐122 and, possibly, some other miRNAs may be efficient for preventing NAFLD‐associated hepatocellular carcinoma. The best candidates for exosome‐wrapped miRNA producer are adipose tissue‐derived mesenchymal stem cells (MSCs), known for their capacity to shed large amounts of exosomes into the media. Notably, MSC‐derived exosomes with no specific loading are already tested in patients with liver fibrosis. Carrier exosomes may be co‐manufactured along with their cargo. Exosome‐delivered miRNA cocktails may augment functioning of human organs suffering from a variety of chronic diseases.

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Section: A Tissue‐cooperative Homeostatic Model Of Non‐alcoholic Fattsupporting

confidence: 85%

Adipose may actively delay progression of NAFLD by releasing tumor‐suppressing, anti‐fibrotic miR‐122 into circulation

2018

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“…However, a common theme in the malignant progression of these tumors is hepatocyte de-differentiation, whereby tumor cells lose the hepatocyte-specific phenotype. These cells proliferate autonomously and acquire the ability to invade and destroy normal tissues [22, 23, 39]. In conclusion, our data suggest that the TT genotype of GSTA1 is associated with an increased risk of occurrence of hepatocellular carcinomas and that decreased expression of GSTA1 is a marker of advanced and highly aggressive hepatocellular carcinomas.…”

Section: Discussionmentioning

confidence: 77%

“…Paraffin-embedded tissue blocks were processed for histology (H&E-Saffran and Sirius red staining), and then classified using standard systems [20, 21]. Fresh mirror image tissue fragments, adjacent to the paraffin-embedded tissue blocks, were snap frozen at -80°C in N 2 -cooled isopentane and stored at -80°C under quality-controlled conditions [22, 23]. White blood cell samples for genotyping were not available for these patients.…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

“…Real-time PCR was performed with the SYBR Green PCR Master Mix (Applied Biosystems) and the ABI prism 7300 PCR station (Applied Biosystems). Primers were previously described [22, 23]. The amplification curves were read with the 7300 SDS software using the comparative cycle threshold method.…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

“…The significance level was set at p<0.05. Gene co-expression networks were generated and visualized as we previously described [22, 23] by Weighted Correlation Network Analysis (WGCNA, WGCNA package) [26] and visually integrated with Cytoscape [27], with correlation coefficient thresholds > 0.40 (positive correlations) or <– 0.40 (negative correlations).…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

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The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals

et al. 2016

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Glutathione S-transferases (GSTs) detoxify toxic molecules by conjugation with reduced glutathione and regulate cell signaling. Single nucleotide polymorphisms (SNPs) of GST genes have been suggested to affect GST functions and thus to increase the risk of human hepatocellular carcinoma (HCC). As GSTA1 is expressed in hepatocytes and the rs3957357C>T (TT) SNP is known to downregulate GSTA1 mRNA expression, the aims of this study were: (i) to explore the relationship between the TT SNP in GSTA1 and the occurrence of HCC; (ii) to measure GSTA1 mRNA expression in HCCs. For that purpose, we genotyped non-tumor-tissue-derived DNA from 48 HCC patients and white-blood-cell-derived DNA from 37 healthy individuals by restriction fragment length polymorphism (RFLP). In addition, expression of GSTA1 mRNA was assessed by real-time PCR in 18 matching pairs of HCCs and non-tumor livers. Survival analysis was performed on an annotated microarray dataset containing 247 HCC patients (GSE14520). The GSTA1 TT genotype was more frequent in HCC than in non-HCC patients (27% versus 5%, respectively), suggesting that individuals carrying this genotype could be associated with 2-fold higher risk of developing HCCs (odds ratio = 2.1; p = 0.02). Also, we found that GSTA1 mRNA expression was lower in HCCs than in non-tumor livers. HCCs expressing the highest GSTA1 mRNA levels were the smallest in size (R = -0.67; p = 0.007), expressed the highest levels of liver-enriched genes such as ALB (albumin, R = -0.67; p = 0.007) and COL18A1 (procollagen type XVIII, R = -0.50; p = 0.03) and showed the most favorable disease-free (OR = 0.54; p<0.001) and overall (OR = 0.56; p = 0.006) outcomes. Moreover, GSTA1 was found within a 263-gene network involved in well-differentiated hepatocyte functions. In conclusion, HCCs are characterized by two GSTA1 features: the TT SNP and reduced GSTA1 gene expression in a context of hepatocyte de-differentiation.

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Myofibroblast‐Specific Msi2 Knockout Inhibits HCC Progression in a Mouse Model

Qu¹,

Hé

Yao³

et al. 2021

Hepatology

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BaCKgRoUND aND aIMS: Myofibroblasts play a pivotal role in the development and progression of HCC. Here, we aimed to explore the role and mechanism of myofibroblast Musashi RNA binding protein 2 (MSI2) in HCC progression. appRoaCH aND ReSUltS: Myofibroblast infiltration and collagen deposition were detected and assessed in the tissues from 117 patients with HCC. Transgenic mice (Msi2 ΔCol1a1 ) with floxed Msi2 allele and collagen type I alpha 1 chain (Col1a1)-ligand inducible Cre recombinases (CreER) were constructed to generate a myofibroblast-specific Msi2 knockout model. Mouse HCC cells were orthotopically transplanted into the Msi2 ΔCol1a1 or the control mice (Msi2 F/F ). We found that the deposition of collagen fibers, the main product of myofibroblasts, predicted a poor prognosis for HCC; meanwhile, we detected high MSI2 expression in the peritumoral infiltrated myofibroblasts. Conditional deletion of Msi2 in myofibroblasts significantly inhibited the growth of orthotopically implanted HCC, reduced both intrahepatic and lung metastasis, and prolonged the overall survival of tumor-bearing mice (P = 0.002). In vitro analysis demonstrated that myofibroblasts promoted cell proliferation, invasion, and epithelialmesenchymal transformation of HCC cells, whereas Msi2 deletion in myofibroblasts reversed these effects. Mechanically, Msi2 knockout decreased myofibroblast-derived IL-6 and IL-11 secretion by inhibiting the extracellular signal-regulated kinase 1/2 pathway, and thus attenuated the cancer stem cell-promoting effect of myofibroblasts. Interestingly, we found that the simultaneous knockout of Msi2 in myofibroblasts and knockdown of Msi2 in HCC cells could not further attenuate the implanted HCC progression.CoNClUSIoNS: Myofibroblast-specific Msi2 knockout abrogated the tumor-promoting function of myofibroblasts and inhibited HCC progression in mouse models. Targeting myofibroblast MSI2 expression may therefore prove to be a therapeutic strategy for HCC treatment in the future.

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“Fibrous nests” in human hepatocellular carcinoma express a Wnt-induced gene signature associated with poor clinical outcome

Cited by 34 publications

References 71 publications

Adipose may actively delay progression of NAFLD by releasing tumor‐suppressing, anti‐fibrotic miR‐122 into circulation

Adipose may actively delay progression of NAFLD by releasing tumor‐suppressing, anti‐fibrotic miR‐122 into circulation

The rs3957357C>T SNP in GSTA1 Is Associated with a Higher Risk of Occurrence of Hepatocellular Carcinoma in European Individuals

Myofibroblast‐Specific Msi2 Knockout Inhibits HCC Progression in a Mouse Model

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