Overexpression of flavin-containing monooxygenase 5 predicts poor prognosis in patients with colorectal cancer

Zhang, Tong; Yang, Ping; Wei, Jianchang; Li, Wanglin; Zhong, Junbin; Chen, Huacui; Cao, Jie

doi:10.3892/ol.2018.7724

Cited by 10 publications

(12 citation statements)

References 22 publications

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“…We further examined additional Myc dependent antisense lncRNAs and their potential target coding RNAs that are downregulated in HCCs. Notably, in HepG2 cells at least 5 Myc dependent antisense noncoding RNAs are detected within Myc dependent coding genes, such as Flavin-containing monooxygenase (FMO)5 13 , zinc finger protein (ZFP) 69 14 , erythroblast membrane-associated protein (ERMAP) 26, and inhibitor of DNA binding (ID)2 15 . In addition, expression of these coding genes is suppressed in HCC, suggesting that these genes may negatively participate in cancer formation.…”

Section: Discussionmentioning

confidence: 99%

Myc/Max dependent intronic long antisense noncoding RNA, EVA1A-AS, suppresses the expression of Myc/Max dependent anti-proliferating gene EVA1A in a U2 dependent manner

Niehus

Allister

Hoffmann

et al. 2019

Sci Rep

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The Myc gene has been implicated in the pathogenesis of most types of human cancerous tumors. Myc/Max activates large numbers of pro-tumor genes; however it also induces anti-proliferation genes. When anti-proliferation genes are activated by Myc, cancer cells can only survive if they are downregulated. Hepatocellular carcinoma (HCC) specific intronic long noncoding antisense (lnc-AS) RNA, the EVA1A-AS gene, is located within the second intron (I2) of the EVA1A gene (EVA-1 homolog A) that encodes an anti-proliferation factor. Indeed, EVA1A, but not EVA1A-AS, is expressed in normal liver. Depletion of EVA1A-AS suppressed cell proliferation of HepG2 cells by upregulation of EVA1A. Overexpression of EVA1A caused cell death at the G2/M phase via microtubule catastrophe. Furthermore, suppressed EVA1A expression levels are negatively correlated with differentiation grade in 365 primary HCCs, while EVA1A-AS expression levels are positively correlated with patient survival. Notably, both EVA1A and EVA1A-AS were activated by the Myc/Max complex. Eva1A-AS is transcribed in the opposite direction near the 3′splice site of EVA1A I2. The second intron did not splice out in a U2 dependent manner and EVA1A mRNA is not exported. Thus, the Myc/Max dependent anti-proliferating gene, EVA1A, is controlled by Myc/Max dependent anti-sense noncoding RNA for HCC survival.

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Section: Discussionmentioning

confidence: 99%

Myc/Max dependent intronic long antisense noncoding RNA, EVA1A-AS, suppresses the expression of Myc/Max dependent anti-proliferating gene EVA1A in a U2 dependent manner

Niehus

Allister

Hoffmann

et al. 2019

Sci Rep

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“…For example, over-expression of SLC29A1, a nucleoside transporter that is capable of both influx and efflux, confers significant resistance to gemcitabine and 5-FU, but little resistance to oxaliplatin or irinotecan. Other genes showing similar patterns include FMO5, a flavin-containing monooxygenase involved in metabolism xenobiotics that has been linked to prognosis in colorectal cancer (Zhang et al, 2018); several genes that function in cellular metabolism: SCD5, HYAC1, COQ6; and other genes involved in transport or its regulation, SLC22A9, SLC16A7, CCZ1, TBC1D3I.…”

Section: Crispr Screening Reveals Drug Resistance Genesmentioning

confidence: 99%

Pooled CRISPR screening in pancreatic cancer cells implicates co-repressor complexes as a cause of multiple drug resistance via regulation of epithelial-to-mesenchymal transition

Ramaker

Hardigan

Gordon

et al. 2019

Preprint

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Chemoresistance is the norm in pancreatic ductal adenocarcinoma (PDAC) leading to an abysmal five-year survival rate of less than 10%. We performed genome-wide CRISPR activation (CRISPRa) and CRISPR knock out (CRISPRko) screens to identify mechanisms of resistance to four cytotoxic chemotherapies (gemcitabine, 5-fluorouracil, irinotecan, and oxaliplatin) used to treat PDAC patients in two PDAC cell lines. Mirroring patient treatment outcomes, we found that multi-drug resistance genes were more likely to be associated with patient survival. We identified activation of ABCG2, a well-described efflux pump, as the most consistent resistance gene in four drugs and two cell lines. Small molecule inhibitors of ABCG2 restored sensitivity to chemotherapy. Our screen demonstrated that activation of members of the hemidesmisome complex and transcriptional repressor complexes conferred resistance to multiple drugs. Finally, we describe an approach for applying our results to predict drug sensitivity in PDAC tumors and cell lines based on gene expression.

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“…Flavin-containing monooxygenases (FMOs) catalyze the ingredients of medicine and diet and have a unique catalytic mechanism [ 11 , 12 ]. Flavin-containing monooxygenase 5 (Fmo5) is a member of the FMOs family, and its expression in the liver tissue of aging mice is lower than that in normal mice [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Kong

Chen

et al. 2021

J Exp Clin Cancer Res

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Background Alcohol-induced intestinal dysbiosis disrupts and inflammatory responses are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigated the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissected the pathogenic role of Fmo5 in AFLD-induced liver pathology. Methods The expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. The WGCNA approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform KEGG pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized using Cytoscape software. The Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expression. ELISA assay was used to detect the levels of serum inflammatory cytokines. Lipid droplets in the cytoplasm were observed using Oil Red O staining. Apoptosis was detected using a TUNEL assay and flow cytometry analysis. ROS levels were detected using flow cytometry analysis. Nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation was used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD. Results Fmo5 is a key DEG and is closely associated with the gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to the PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal models with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. The NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury. Conclusion Our data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition and alleviated AFLD-induced liver injury, apoptosis, and inflammatory response by inhibiting the nuclear translocation of NF-κB p65 to inhibit the NF-κB signaling pathway.

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Overexpression of flavin-containing monooxygenase 5 predicts poor prognosis in patients with colorectal cancer

Cited by 10 publications

References 22 publications

Myc/Max dependent intronic long antisense noncoding RNA, EVA1A-AS, suppresses the expression of Myc/Max dependent anti-proliferating gene EVA1A in a U2 dependent manner

Myc/Max dependent intronic long antisense noncoding RNA, EVA1A-AS, suppresses the expression of Myc/Max dependent anti-proliferating gene EVA1A in a U2 dependent manner

Pooled CRISPR screening in pancreatic cancer cells implicates co-repressor complexes as a cause of multiple drug resistance via regulation of epithelial-to-mesenchymal transition

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

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