A pro-tumorigenic function of S100A8/A9 in carcinogen-induced hepatocellular carcinoma

Ponti, Aurora De; Wiechert, Lars; Schneller, Doris; Pusterla, Tobias; Longerich, Thomas; Hogg, Nancy; Vogel, Arndt; Schirmacher, Peter; Heß, Jochen; Angel, Peter

doi:10.1016/j.canlet.2015.09.005

Cited by 34 publications

(34 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Calprotectin has recently been shown to play a protumorigenic function in diethylnitrosamine-induced mouse hepatocarcinogenesis. 27 Our results also demonstrated that the mRNA expression of Psat1 and Phgdh was suppressed by MadMyc induction, suggesting that serine biosynthesis, which is crucial in glutathione synthesis, 34 could be a therapeutic target. On the other hand, MadMyc induction recovered the mRNA expression of Cyp1a2 and Ppp1r3g .…”

Section: Discussionsupporting

confidence: 56%

“…Interestingly, Dox treatment reduced the mRNA expression of Afp , Slpi , Gpc3 and H19 , which are expressed in the fetal/neonatal liver and activated in CCl 4 − or diethylnitrosamine-induced liver tumours. 26 The induction of MadMyc suppressed the mRNA expression of S100a9 and S100a8 , which encodes calprotectin, 27 a heterodimeric protumorigenic protein, as well as that of Psat1 and Phgdh whose products are involved in serine biosynthesis. The detection of transcripts of the genes for immunoglobulin and immune functions in the tumours was attributable to inflammatory cell infiltrates frequently found in the tumours with induced MadMyc ( Figure 4b ).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways

et al. 2017

View full text Add to dashboard Cite

MYC activation at modest levels has been frequently found in hepatocellular carcinoma. However, its significance in hepatocarcinogenesis has remained obscure. Here we examined the role of Myc activation in mouse liver tumours induced by hepatocytic expression of myristoylated AKT (AKT) and/or mutant HRASV12 (HRAS) via transposon-mediated gene integration. AKT or HRAS alone required 5 months to induce liver tumours, whereas their combination generated hepatocellular carcinoma within 8 weeks. Co-introduction of AKT and HRAS induced lipid-laden preneoplastic cells that grew into nodules composed of tumour cells with or without intracytoplasmic lipid, with the latter being more proliferative and associated with spontaneous Myc expression. AKT/HRAS-induced tumorigenesis was almost completely abolished when MadMyc, a competitive Myc inhibitor, was expressed simultaneously. The Tet-On induction of MadMyc in preneoplastic cells significantly inhibited the progression of AKT/HRAS-induced tumours; its induction in transformed cells suppressed their proliferative activity with alterations in lipid metabolism and protein translation. Transposon-mediated Myc overexpression facilitated tumorigenesis by AKT or HRAS, and when it was co-introduced with AKT and HRAS, diffusely infiltrating tumours without lipid accumulation developed as early as 2 weeks. Examination of the dose-responses of Myc in the enhancement of AKT/HRAS-induced tumorigenesis revealed that a reduction to one-third retained enhancing effect but three-times greater introduction damped the process with increased apoptosis. Myc overexpression suppressed the mRNA expression of proteins involved in the synthesis of fatty acids, and when combined with HRAS introduction, it also suppressed the mRNA expression of proteins involved in their degradation. Finally, the MYC-positive human hepatocellular carcinoma was characterized by the cytoplasm devoid of lipid accumulation, prominent nucleoli and a higher proliferative activity. Our results demonstrate that in hepatocarcinogenesis induced by both activated AKT and HRAS, activation of endogenous Myc is an enhancing factor and adequate levels of Myc deregulation further facilitate the process with alterations in cellular metabolism.

show abstract

Section: Discussionsupporting

confidence: 56%

Section: Resultsmentioning

confidence: 99%

Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways

et al. 2017

View full text Add to dashboard Cite

show abstract

“…S100A8 and S100A9 are NF-kappa B target genes during malignant progression of inflammation-associated liver carcinogenesis 22 . The absence of S100A8/A9 could significantly reduce the tumor size in HCC model 23 . S100A8, as an endogenous ligand for toll-like receptor 4, contributes to lung metastasis 24 .…”

Section: Discussionmentioning

confidence: 92%

Quantitative Proteomics Analysis of Tissue Interstitial Fluid for Identification of Novel Serum Candidate Diagnostic Marker for Hepatocellular Carcinoma

Sun

Xing

Guo³

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is the fifth most common malignant cancer in the world. The sensitivity of alpha-fetoprotein (AFP) is still inadequate for HCC diagnosis. Tissue interstitial fluid (TIF), as the liquid microenvironment of cancer cells, was used for biomarker discovery in this study. Paired tumor and nontumor TIF samples from 6 HBV-HCC patients were analyzed by a proteomic technique named iTRAQ (isobaric tag for relative and absolute quantitation). Totally, 241 up-regulated proteins (ratio ≥ 1.3, p < 0.05) and 288 down-regulated proteins (ratio ≤ −1.3, p < 0.05) in tumor TIF were identified. Interestingly, proteins in S100 family were found remarkably up-regulated in tumor TIF. One dramatically up-regulated protein S100A9 (ratio = 19) was further validated by ELISA in sera from liver cirrhosis (LC, HCC high risk population) and HCC patients (n = 47 for each group). The level of this protein was significantly elevated in HCC sera compared with LC (p < 0.0001). The area under the curve of this protein to distinguish HCC from LC was 0.83, with sensitivity of 91% (higher than AFP) and specificity of 66%. This result demonstrated the potential of S100A9 as a candidate HCC diagnostic biomarker. And TIF was a kind of promising material to identify candidate tumor biomarkers that could be detected in serum.

show abstract

“…S100A8 gene is a member of the S100 family, and has been reported to be over-expressed in various kinds of cancer [ 17 , 18 ]. Previous studies suggested that S100A8 plays key roles in modulation of inflammation and immune response, which is conducive to genesis of almost all tumors [ 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

Targeted Silencing of S100A8 Gene by miR-24 to Increase Chemotherapy Sensitivity of Endometrial Carcinoma Cells to Paclitaxel

Liu

Shang²,

2016

Med Sci Monit

View full text Add to dashboard Cite

BackgroundThe objective of this study was to determine whether miR-24 can regulate malignant proliferation and chemotherapy sensitivity of EC cells by targeted silencing of the S100 Calcium Binding Protein A8 (S100A8) gene.Material/MethodsThe expression of miR-24 in EC tissues was detected by quantitative real-time PCR. The proliferation ability and chemotherapy sensitivity were analyzed by MTT assay. Bioinformatics software was used to predict some potential target genes of miR-24. Luciferase activity assay was used to verify the relationship between target genes and miR-24. S100A8 protein expression was detected by Western blot analysis.ResultsThe low expression of miR-24 in EC tissues compared with normal control tissues suggests miR-24 might play a role in tumorigenesis of EC. EC HEC-1A cells were transfected with miR-24 agonist (agomiR-24) to up-regulate the expression of miR-24. Up-regulation of miR-24 inhibited the cell proliferation and advanced the chemotherapy sensitivity to paclitaxel in HEC-1A cells significantly. We used several types of bioinformatic software to predict that miR-24 could specifically combine with the 3′ untranslated region (3′UTR) of the S100A8 gene, and this prediction was verified by Western blot and luciferase activities assay. The regulation effects of miR-24 enhancement on cell proliferation and chemotherapy sensitivity were largely reversed by S100A8 up-regulation.ConclusionsmiR-24 acts as a tumor-suppressing gene to inhibit malignant proliferation and advance chemotherapy sensitivity to paclitaxel in EC by targeted silencing of the S100A8 gene.

show abstract

A pro-tumorigenic function of S100A8/A9 in carcinogen-induced hepatocellular carcinoma

Cited by 34 publications

References 46 publications

Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways

Critical role of Myc activation in mouse hepatocarcinogenesis induced by the activation of AKT and RAS pathways

Quantitative Proteomics Analysis of Tissue Interstitial Fluid for Identification of Novel Serum Candidate Diagnostic Marker for Hepatocellular Carcinoma

Targeted Silencing of S100A8 Gene by miR-24 to Increase Chemotherapy Sensitivity of Endometrial Carcinoma Cells to Paclitaxel

Contact Info

Product

Resources

About