Differential Expression of Long Noncoding RNAs in the Livers of Female B6C3F1 Mice Exposed to the Carcinogen Furan

Recio, Leslie; Phillips, Suzanne; Maynor, Timothy; Waters, Michael D.; Jackson, Anna Francina; Yauk, Carole L.

doi:10.1093/toxsci/kft153

Cited by 30 publications

(31 citation statements)

References 31 publications

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“…Here, using RNA sequence, we identified differentially expressed lincRNA-p21 in hepatocyte during liver fibrosis. Similarly, lincRNA-p21 increased in the livers of mice treated with the carcinogen furan, and thus implying an extensive role of lincRNA-p21 in the response to liver injury 38 . Of note, lincRNA-p21 also increased and contributed to pulmonary fibrosis in acute respiratory distress syndrome 39 .…”

Section: Discussionmentioning

confidence: 95%

TGF-β-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice

Zhang

Zheng

et al. 2017

Sci Rep

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Hepatocyte death, as well as the following inflammatory and fibrogenic signaling cascades, is the key trigger of liver fibrosis. Here, we isolated hepatocytes from CCl4-induced fibrotic liver and found that hepatocyte lincRNA-p21 significantly increased during liver fibrosis. The increase of hepatocyte lincRNA-p21 was associated with the loss of miR-30, which can inhibit TGF-β signaling by targeting KLF11. We revealed that lincRNA-p21 modulated miR-30 availability by acting as a competing endogenous RNA (ceRNA). The physiological significance of this interaction is highlighted by the feedback loop, in which lincRNA-p21 works as a downstream effector of the TGF-β signaling to strengthen TGF-β signaling and mediate its role in promoting liver fibrosis by interacting with miR-30. In vivo results showed that knockdown of hepatocyte lincRNA-p21 greatly reduced CCl4-induced liver fibrosis and inflammation, whereas ectopic expression of miR-30 in hepatocyte exhibited the similar results. Mechanistic studies further revealed that inhibition of miR-30 impaired the effects of lincRNA-p21 on liver fibrosis. Additionally, lincRNA-p21 promoted hepatocyte apoptosis in vitro and in vivo, whereas the proliferation rate of hepatocyte was suppressed by lincRNA-p21. The pleiotropic roles of hepatocyte lincRNA-p21 suggest that it may represent an unknown paradigm in liver fibrosis and serve as a potential target for therapy.

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Section: Discussionmentioning

confidence: 95%

TGF-β-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice

Zhang

Zheng

et al. 2017

Sci Rep

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“…Genome-wide gene expression analysis was performed using Superprint G3 Human GE 8×60k Microarray (Agilent Technologies) as previously described [59]. …”

Section: Methodsmentioning

confidence: 99%

MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells

et al. 2014

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MicroRNA-101 has been implicated as a tumor suppressor miRNA in human tumors. However, its potential functional impact and the underlying mechanisms in endometrial cancer progression have not been determined. Here, we report that in aggressive endometrial cancer cells, re-expression of microRNA-101 leads to inhibition of cell proliferation and induction of apoptosis and senescence. Ectopic overexpression of microRNA-101 attenuates the epithelial-mesenchymal transition-associated cancer cell migration and invasion, abrogates the sphere-forming capacity and enhances chemosensitivity to paclitaxel. Algorithm and microarray-based strategies identifies potential microRNA-101 targets. Among these, we validated EZH2, MCL-1 and FOS as direct targets of miR-101 and silencing of these genes mimics the tumor suppressive effects observed on promoting microRNA-101 function. Importantly, further results suggest an inverse correlation between low miR-101 and high EZH2, MCL-1 and FOS expression in EC specimens. We conclude that, as a crucial tumor suppressor, microRNA-101 suppresses cell proliferation, invasiveness and self-renewal in aggressive endometrial cancer cells via modulating multiple critical oncogenes. The microRNA-101-EZH2/MCL-1/FOS axis is a potential therapeutic target for endometrial cancer.

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“…Furan is a well-characterized hepatotoxicant with an extensive toxicological literature, including two cancer bioassays (NTP 1993; Moser et al 2009) and many xenobiotic metabolism (Burka et al 1991; Kedderis et al 1993; Carfagna et al 1993; Chen et al 1995; Kedderis and Held 1996; Mugford et al 1997; Chen et al 1997; Gates et al 2012), genotoxicity (Peterson et al 2000; Byrns et al 2002; Byrns et al 2006; Durling et al 2007; Kellert et al 2008; Leopardi et al 2010; Cordelli et al 2010; Neuwirth et al 2012; McDaniel et al 2012; Ding et al 2012), mode of action (Fransson-Steen et al 1997; Moser et al 2009; Hickling et al 2010; Carthew et al 2010; Moro et al 2012b), and exposure/risk (Heppner and Schlatter 2007; Gill et al 2010; Gill et al 2011; Moro et al 2012a) studies, making it an excellent test compound for a retrospective FFPE genomics case study. We recently characterized early molecular key events in the mode of action of furan in female mice using fresh-frozen livers and identified a key role for the Nrf2 Oxidative Stress Response pathway (Jackson et al 2014; Recio et al 2013). Oxidative stress and damage have been previously reported in response to Cyp2E1 activity and cellular exposure to BDA (furan’s cytotoxic primary metabolite) (Chen et al 1998; Marí et al 2001; Cederbaum et al 2001; Gonzalez 2005; Gong and Cederbaum 2006; Lu and Cederbaum 2008; Hickling et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Mining the archives: a cross-platform analysis of gene expression profiles in archival formalin-fixed paraffin-embedded (FFPE) tissue

Webster

Zumbo

Fostel

et al. 2015

Preprint

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Formalin-fixed paraffin-embedded (FFPE) tissue samples represent a potentially invaluable resource for transcriptomic-based research into the molecular basis of disease. However, use of FFPE samples in gene expression studies has been limited by technical challenges resulting from degradation of nucleic acids. Here we evaluated gene expression profiles derived from fresh-frozen (FRO) and FFPE mouse liver tissues using two DNA microarray protocols and two whole transcriptome sequencing (RNA-seq) library preparation methodologies. The ribo-depletion protocol outperformed the other three methods by having the highest correlations of differentially expressed genes (DEGs) and best overlap of pathways between FRO and FFPE groups. We next tested the effect of sample time in formalin (18 hours or 3 weeks) on gene expression profiles. Hierarchical clustering of the datasets indicated that test article treatment, and not preservation method, was the main driver of gene expression profiles. Meta- and pathway analyses indicated that biological responses were generally consistent for 18-hour and 3-week FFPE samples compared to FRO samples. However, clear erosion of signal intensity with time in formalin was evident, and DEG numbers differed by platform and preservation method. Lastly, we investigated the effect of age in FFPE block on genomic profiles. RNA-seq analysis of 8-, 19-, and 26-year-old control blocks using the ribo-depletion protocol resulted in comparable quality metrics, including expected distributions of mapped reads to exonic, UTR, intronic, and ribosomal fractions of the transcriptome. Overall, our results suggest that FFPE samples are appropriate for use in genomic studies in which frozen samples are not available, and that ribo-depletion RNA-seq is the preferred method for this type of analysis in archival and long-aged FFPE samples.

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Differential Expression of Long Noncoding RNAs in the Livers of Female B6C3F1 Mice Exposed to the Carcinogen Furan

Cited by 30 publications

References 31 publications

TGF-β-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice

TGF-β-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice

MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells

Mining the archives: a cross-platform analysis of gene expression profiles in archival formalin-fixed paraffin-embedded (FFPE) tissue

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