Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation

Bakiri, Latifa; Hamacher, Rainer; Graña, Osvaldo; Guío-Carrión, Ana; Campos-Olivas, Ramón; Martínez, Lola; Dienes, Hans Peter; Thomsen, Martin K.; Hasenfuss, Sebastian C.; Wagner, Erwin F.

doi:10.1084/jem.20160935

Cited by 97 publications

(85 citation statements)

References 93 publications

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“…A study by Guo J et al showed that the expression of c-FOS in the tumor tissues of pancreatic cancer seemed to be lower than that in adjacent nontumor tissues [ 34 ]. However, some other research showed that FOS could contribute to carcinogenesis [ 35 , 36 ]. Therefore, the above research work indicated that c-FOS is expressed differently in different histological types and is closely related to the proliferation, differentiation, invasion, and apoptosis of tumor cells, which provided a new therapeutic target for cancer by regulating the expression of c-FOS.…”

Section: Discussionmentioning

confidence: 99%

Analysis of Transcription Factor-Related Regulatory Networks Based on Bioinformatics Analysis and Validation in Hepatocellular Carcinoma

Shui

Yao

Zhang

et al. 2018

BioMed Research International

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Hepatocellular carcinoma (HCC) accounts for a significant proportion of liver cancer, which has become the second most common cause of cancer-related mortality worldwide. To investigate the potential mechanisms of invasion and progression of HCC, bioinformatics analysis and validation by qRT-PCR were performed. We found 237 differentially expressed genes (DEGs) including EGR1, FOS, and FOSB, which were three cancer-related transcription factors. Subsequently, we constructed TF-gene network and miRNA-TF-mRNA network based on data obtained from mRNA and miRNA expression profiles for analysis of HCC. We found that 42 key genes from the TF-gene network including EGR1, FOS, and FOSB were most enriched in the p53 signaling pathway. The qRT-PCR data confirmed that mRNA levels of EGR1, FOS, and FOSB all were decreased in HCC tissues. In addition, we confirmed that the mRNA levels of CCNB1, CCNB2, and CHEK1, three key markers of the p53 signaling pathway, were all increased in HCC tissues by bioinformatics analysis and qRT-PCR validation. Therefore, we speculated that miR-181a-5p, which was upregulated in HCC tissues, could regulate FOS and EGR1 to promote the invasion and progression of HCC by p53 signaling pathway. Overall, the study provides support for the possible mechanisms of progression in HCC.

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Section: Discussionmentioning

confidence: 99%

Analysis of Transcription Factor-Related Regulatory Networks Based on Bioinformatics Analysis and Validation in Hepatocellular Carcinoma

Shui

Yao

Zhang

et al. 2018

BioMed Research International

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“…This upregulation of the mevalonate pathway further upregulates the microRNA miR-33b, thus increasing MYC expression and establishing a positive feedback loop facilitating tumour growth. In hepatocytes, transgenic expression of the oncogene c-Fos represses LXRα signalling and elevates the production of cholesterol and cholesterol-derived metabolites such as oxysterols and bile acids 62 , which in turn is associated with increased inflammation and hepatocellular carcinogenesis. Whereas oncogene activity promotes cholesterol upregulation, tumour suppressors have the opposite effect.…”

Section: Enriched Cholesterol Derivatives: Cholesteryl Esters and Oxymentioning

confidence: 99%

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

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C holesterol is vital for the survival and growth of mammalian cells. More than a membrane constituent, cholesterol is a precursor to bile acids and steroid hormones, which can initiate or promote colon, breast and prostate cancers 1-3 . Cholesterol can also modulate signalling pathways involved in tumourigenesis and cancer progression by covalently modifying proteins including hedgehog and smoothened 4,5 , and by facilitating the formation of specialized membrane microdomains 6,7 . Brief overview of cholesterol metabolismEvery mammalian cell can synthesize cholesterol through the mevalonate pathway (Fig. 1a). Two acetyl-CoA molecules in the cytosol condense, thus forming acetoacetyl-CoA, which reacts with the third acetyl-CoA and yields 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is reduced to mevalonate by HMG-CoA reductase (HMGCR), the primary rate-limiting enzyme in cholesterol biosynthesis. A series of enzymatic reactions convert mevalonate to farnesyl pyrophosphate (FPP), a precursor of sterols and all non-sterol isoprenoids. The condensation of two FPP molecules to squalene commits the process to sterol production. FPP also gives rise to geranylgeranyl pyrophosphate (GGPP), and both FPP and GGPP can prenylate and activate several oncogenic proteins such as Ras 8 . Squalene is then oxidized by squalene epoxidase (SQLE) to 2,3-epoxysqualene, which is cyclized to lanosterol. In the next steps, lanosterol follows the Bloch pathway, the Kandutsch-Russell pathway or a hybrid pathway before it is finally converted to cholesterol.Beyond de novo cholesterol biosynthesis, most cells acquire cholesterol from low-density lipoprotein (LDL) taken up from the circulation via LDL receptor (LDLR)-mediated endocytosis 9 . Enterocytes absorb dietary cholesterol from the intestinal lumen in a process involving the cholesterol transporter NPC1L1, the clathrin adaptor NUMB and the adaptor protein LIMA1 (refs. 10-12 ). Cholesterol within the cell is dynamically transported, reaching the destined membranes for structural and functional needs 13 . Cholesterol in excess of the current cellular demand is either exported from the cell by ATP-binding cassette (ABC) transporters, Reprogrammed cholesterol metabolism in cancer cellsHallmark features of cancer cholesterol metabolism. As fastproliferating cells, cancer cells require high levels of cholesterol for membrane biogenesis and other functional needs. For example, the cholesterol-derived oncometabolite 6-oxo-cholestan-3β,5α-diol, which is enriched in patients with breast cancer, binds glucocorticoid receptors and subsequently promotes tumour growth 19 . In general, cholesterol metabolism substantially contributes to cancer progression, including cell proliferation, migration and invasion 20-23 .Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-de...

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“…36,37 Studies have shown that the absence of specific c-Fos in HCC cells can prevent dEn-induced HCC, while liver-specific c-Fos Expression can lead to cell carcinogenesis and enhanced carcinogenesis of dEn. 38 Meanwhile, it has been reported that IL-11 could promote the progression of colorectal cancer, breast cancer and gastric cancer. 39 It was also showed that IL11could participate in the regulation pathways in HCC recurrence and…”

Section: Discussionmentioning

confidence: 99%

Seven immune‐related genes prognostic power and correlation with tumor‐infiltrating immune cells in hepatocellular carcinoma

Liu

et al. 2020

Cancer Medicine

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Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation

Cited by 97 publications

References 93 publications

Analysis of Transcription Factor-Related Regulatory Networks Based on Bioinformatics Analysis and Validation in Hepatocellular Carcinoma

Analysis of Transcription Factor-Related Regulatory Networks Based on Bioinformatics Analysis and Validation in Hepatocellular Carcinoma

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Seven immune‐related genes prognostic power and correlation with tumor‐infiltrating immune cells in hepatocellular carcinoma

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