Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels

Li, Changfei; Deng, Mengmeng; Hu, Jun; Li, Xin; Chen, Lizhao; Ju, Ying; Hao, Junli; Meng, Songdong

doi:10.18632/oncotarget.7740

Cited by 60 publications

(43 citation statements)

References 40 publications

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“…IL-1β, TNF-α, and LPS are known to have potent effects on the invasiveness of RA-FLS. In human neurons, GLS1 expression was upregulated by IL-1β or TNF-α treatment, and in a rat hepatoma model IL-6 or TNF-α treatment indirectly upregulated c-MYC expression [49, 50]. However, we did not observe upregulation of GLS1 by IL-1β, TNF-α, or LPS.…”

Section: Discussioncontrasting

confidence: 54%

Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis

et al. 2017

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BackgroundThe recent findings of cancer-specific metabolic changes, including increased glucose and glutamine consumption, have provided new therapeutic targets for consideration. Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients exhibit several tumor cell-like characteristics; however, the role of glucose and glutamine metabolism in the aberrant proliferation of these cells is unclear. Here, we evaluated the role of these metabolic pathways in RA-FLS proliferation and in autoimmune arthritis in SKG mice.MethodsThe expression of glycolysis- or glutaminolysis-related enzymes was evaluated by real-time polymerase chain reaction (PCR) and Western blotting, and the intracellular metabolites were evaluated by metabolomic analyses. The effects of glucose or glutamine on RA-FLS cell growth were investigated using glucose- or glutamine-free medium. Glutaminase (GLS)1 small interfering RNA (siRNA) and the GLS1 inhibitor compound 968 were used to inhibit GLS1 in RA-FLS, and compound 968 was used to study the effect of GLS1 inhibition in zymosan A-injected SKG mice.ResultsGLS1 expression was increased in RA-FLS, and metabolomic analyses revealed that glutamine metabolism was increased in RA-FLS. RA-FLS proliferation was reduced under glutamine-deprived, but not glucose-deprived, conditions. Cell growth of RA-FLS was inhibited by GLS1 siRNA transfection or GLS1 inhibitor treatment. Treating RA-FLS with either interleukin-17 or platelet-derived growth factor resulted in increased GLS1 levels. Compound 968 ameliorated the autoimmune arthritis and decreased the number of Ki-67-positive synovial cells in SKG mice.ConclusionsOur results suggested that glutamine metabolism is involved in the pathogenesis of RA and that GLS1 plays an important role in regulating RA-FLS proliferation, and may be a novel therapeutic target for RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1283-3) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 54%

Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis

et al. 2017

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“…The CCL2 expression in the liver was enhanced in one model but not in the other. Later, another group briefly reported that the decrease of miR-122 may cause an upregulation of CCL2 [30]. In the present study, our data demonstrates that the downregulation of miR-122 mediated the upregulation of CCL2 by directly binding to the 3’ UTR of CCL2 mRNA.…”

Section: Discussionsupporting

confidence: 69%

CCL2 is Upregulated by Decreased miR-122 Expression in Iron-Overload-Induced Hepatic Inflammation

Tang¹,

Jia²,

Niu³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Iron overload (IO) is accompanied by hepatic inflammation. The chemokine (C-C motif) ligand 2 (CCL2) mediates inflammation, and its overexpression is associated with IO. However, whether IO results in CCL2 overexpression in the liver and the underlying mechanisms are unclear. Methods: We subjected mice to IO by administering intraperitoneal injections of dextran-iron or by feeding mice a 3% dextran-iron diet to observe the effects of IO on miR-122/CCL2 expression through real-time qPCR and Western blot analysis. We also used indicators, including the expression of the inflammatory cytokine, the inflammation score based on H&E staining and the serum content of ALT and AST to evaluate the effects of IO on hepatic inflammation. Meanwhile, we observed the effects of vitamin E on IO-induced hepatic inflammation. In cells, we used 100 µΜ FeSO₄ or 30 µΜ Holo-Tf to produce IO and observed the roles of miR-122 in regulating CCL2 expression by using miR-122 mimics or inhibitors to overexpress or inhibit miR-122. Then, we used a dual-luciferase reporter assay to prove that miR-122 regulates CCL2 expression through direct binding to its complementary sequence in the CCL2 mRNA 3’UTR. Results: IO induces the downregulation of miR-122 and the upregulation of CCL2, as well as inflammatory responses both in vitro and in vivo. Although IO-induced oxidative stress is eliminated by the antioxidant vitamin E, IO-induced hepatic inflammation still exists, which probably can be explained by the fact that vitamin E has no effects on the miR-122/CCL2 pathway. In in vitro experiments, the overexpression and inhibition of miR-122 significantly reduced and increased CCL2 expression, respectively. The dual-luciferase reporter assay indicates that miR-122 binds CCL2 mRNA 3’UTR. Conclusion: We propose the roles of miR-122/CCL2 in IO-induced hepatic inflammation. Our studies should provide a new clue for developing clinical strategies for patients with IO.

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“…In recent years, increasing evidence suggested that miR-122 plays an important role in initiation and progression of HCC. Li et al 117 found that miR-122 expression is low in patients with chronic hepatitis B and HCC tumors and has negative correlation with fibrotic stage, age, and liver transaminase levels. The downregulation of miR-122 in patients with chronic hepatitis B and HCC tissues is affected by HBV infection.…”

Section: Mirnas Are a Novel Class Of Molecules Linking Inflammation Amentioning

confidence: 99%

“…The reduced miR-122 expression in HCC tissues is characterized by a poor prognosis and consistent with a suppressed hepatic phenotype and an increased metastatic potential 121 . Moreover, miR-122 expression can be suppressed by two inflammatory cytokines, IL-6 and TNF-α, which downregulate the miR-122 transcription factors C/EBPα and HNF3β and induce c-myc-mediated C/EBPα inhibition in chronic hepatic inflammation 117 . MiR-122 downregulation results in the upregulation of target genes that promote hepatocarcinogenesis, including pituitary tumor trans-forming gene binding factor (PBF), cyclin G1, PKM2, ADAM10, ADAM17, SRF, and PKR activator 122-124 .…”

Section: Mirnas Are a Novel Class Of Molecules Linking Inflammation Amentioning

confidence: 99%

Role of microRNAs in inflammation-associated liver cancer

Huan

Liang

2016

Cancer Biology & Medicine

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Liver cancer, primarily hepatocellular carcinoma (HCC), is a major cause of cancer-related death worldwide. HCC is a suitable model of inflammation-induced cancer because more than 90% of HCC cases are caused by liver damage and chronic inflammation. Several inflammatory response pathways, such as NF-κB and JAK/STAT3 signaling pathways, play roles in the crosstalk between inflammation and HCC. MicroRNAs (miRNAs) are evolutionarily conserved, short endogenous, non-coding single-stranded RNAs that are involved in various biological and pathological processes by regulating gene expression and protein translation. Evidence showed that miRNAs play a pivotal role in hepatitis virus infection and serve as promoters or inhibitors of inflammatory response. Aberrant miRNA was observed during liver inflammation and HCC. Many dysregulated miRNAs modulate the initiation and progression of inflammation-induced HCC. This review summarizes the role and functions of miRNAs in inflammation-associated HCC, as well as the designed therapeutics targeting miRNAs to treat liver inflammation and HCC.

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Chronic inflammation contributes to the development of hepatocellular carcinoma by decreasing miR-122 levels

Cited by 60 publications

References 40 publications

Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis

Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis

CCL2 is Upregulated by Decreased miR-122 Expression in Iron-Overload-Induced Hepatic Inflammation

Role of microRNAs in inflammation-associated liver cancer

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