Regulation of the Extrinsic Apoptotic Pathway by MicroRNA-21 in Alcoholic Liver Injury

Francis, Heather; McDaniel, Kelly; Han, Yuyan; Liu, Xiuping; Kennedy, Lindsey; Yang, Fuquan; McCarra, Jennifer; Zhou, Tianhao; Glaser, Shannon; Venter, Julie; Huang, Li; Levine, Peter M.; Lai, Jia Ming; Liu, Chang Gong; Alpini, Gianfranco; Meng, Fanyin

doi:10.1074/jbc.m114.602383

Cited by 78 publications

(78 citation statements)

References 45 publications

(48 reference statements)

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“…The miR-21 inhibitor contains a sequence that is 100% complementary to the sequence of active miR-21; therefore, binding between the inhibitor and miR-21 should be highly specific. As well, we have previously shown that use of this inhibitor in vitro is able to increase hepatocyte and HSC expression of DR5 and Fas ligand, known targets of miR-21, by approximately two fold 26 . Unfortunately, since the inhibitor only binds to activated forms of miR-21 we are unable to accurately detect miR-21 expression levels since you may still get signals from the gene encoding miR-21, pri-miR-21, and pre-miR-21.…”

Section: Methodsmentioning

confidence: 76%

“…MicroRNA21 (miR-21) knockout (miR-21 −/− ) mice and background-matched miR-21 +/+ (wild-type, (WT), strain B6; 129) mice were purchased from Jackson Laboratory (Sacramento, CA); the breeding colony is established in our animal facility. No gross defects or phenotypical changes are noted in the miR-21 −/− mice 26 . Male FVB/NJ WT mice (control for Mdr2 −/− mice) were purchased from Jackson Laboratory.…”

Section: Methodsmentioning

confidence: 89%

“…Previously, we have shown that miR-21 is upregulated in a model of alcoholic liver injury and decreases HSC apoptosis 26 . However, this study did not delve into the role of miR-21 on cholangiocytes during injury or HSC-promoted fibrosis.…”

Section: Introductionmentioning

confidence: 94%

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Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice

Kennedy

Meng

Venter

et al. 2016

Laboratory Investigation

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Cholestasis is a condition that leads to chronic hepatobiliary inflammation, fibrosis, and eventually cirrhosis. Many microRNAs (miRs) are known to play a role in fibrosis progression; however, the role of miR-21 during cholestasis remains unknown. Therefore, the aim of this study was to elucidate the role of miR-21 during cholestasis-induced biliary hyperplasia and hepatic fibrosis. Wild-type (WT) and miR21−/− mice underwent sham or bile duct ligation (BDL) for 1 wk, before evaluating liver histology, biliary proliferation, hepatic stellate cell (HSC) activation, fibrotic response, and Smad-7 expression. In vitro, immortalized murine biliary cell lines (IMCL) and human hepatic stellate cell line (hHSC) were treated with either miR-21 inhibitor or control before analyzing proliferation, apoptosis, and fibrotic responses. In vivo, the levels of miR-21 were increased in total liver and cholangiocytes after BDL, and loss of miR-21 decreased the amount of BDL-induced biliary proliferation and intrahepatic biliary mass. Also, loss of miR-21 decreased BDL-induced HSC activation, collagen deposition, and expression of the fibrotic markers TGF-β1 and α-SMA. In vitro, IMCL and hHSCs treated with miR-21 inhibitor displayed decreased proliferation and expression of fibrotic markers and enhanced apoptosis when compared to control treated cells. Furthermore, mice lacking miR-21 show increased Smad-7 expression, which may be driving the decrease in biliary hyperplasia and hepatic fibrosis. During cholestatic injury miR-21 is increased and leads to increased biliary proliferation and hepatic fibrosis. Local modulation of miR-21 may be a therapeutic option for patients with cholestasis.

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Section: Methodsmentioning

confidence: 76%

Section: Methodsmentioning

confidence: 89%

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Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice

Kennedy

Meng

Venter

et al. 2016

Laboratory Investigation

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“…Thyroid hormone (T3) increased transcript levels of both miR-21 and the TMEM49/VMP1 gene in which it is encoded in HepG2 cells stably overexpressing thyroid hormone receptor ␣1 (TR␣1) or TR␤1 (25). IL-6 was reported to increase miR-21 in normal human hepatocytes by activating Stat3 recruitment to the miR-21 promoter (21). We recently reported that DHEA was metabolized to steroids, increasing AR and ER␤ recruitment to the miR-21 promoter, resulting in increased primary miR-21 (pri-miR-21) transcription after 6 h of treatment in HepG2 cells (26).…”

mentioning

confidence: 99%

“…19). miR-21 is 1 of the 10 most abundant miRNAs in human and mouse liver (20) and is an established survival factor during liver injury and HCC development (21). miR-21 down-regulates the expression of a number of tumor suppressor proteins, e.g.…”

mentioning

confidence: 99%

Dehydroepiandrosterone Activation of G-protein-coupled Estrogen Receptor Rapidly Stimulates MicroRNA-21 Transcription in Human Hepatocellular Carcinoma Cells

Teng

Radde

Litchfield

et al. 2015

Journal of Biological Chemistry

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Background: is an oncomiR in human hepatocellular carcinoma and is highly expressed in liver, but its regulation is uncharacterized. Results: Dehydroepiandrosterone (DHEA) rapidly increases miR-21 transcription in HepG2 cells by activating G-proteincoupled estrogen receptor (GPER). Conclusion: miR-21 transcription is regulated by DHEA through GPER. Significance: GPER may be among the activators of miR-21 expression in human hepatocellular carcinoma.

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Noncoding RNAs in development and teratology, with focus on effects of cannabis, cocaine, nicotine, and ethanol

Pinson

Miranda

2019

Birth Defects Research

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Completion of the Human Genome Project has led to the identification of a large number of transcription start sites that are not paired with protein‐coding genes, supporting the growing recognition of the abundance of encoded nonprotein‐coding RNAs (ncRNAs) and their importance for speciation and species‐specific development. Present in both plants and animals, ncRNAs vary in size, function, primary sequence, and secondary structure. While microRNAs (miRNAs) are the best known, there are a number of other ncRNAs (long[er] nonprotein‐coding RNA, pseudogenes, circular RNAs, and so on) that have been shown to play an important role in the development either directly or via networks of proteins and other ncRNAs, including modulating the impact of miRNAs. Furthermore, these ncRNAs and their developmental regulatory networks are sensitive to teratogens such as ethanol, cannabis, cocaine, and nicotine. A better understanding of the developmental role of ncRNAs and their capacity to mediate teratogenesis is a necessary step in efforts to minimize the long‐term consequences of developmental exposures to drugs‐of‐abuse. Moreover, with increasing awareness of the prevalence of polydrug use, experimental models will need to incorporate more complex drug exposure paradigms into meaningful assessments of developmental ncRNA function.

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Regulation of the Extrinsic Apoptotic Pathway by MicroRNA-21 in Alcoholic Liver Injury

Cited by 78 publications

References 45 publications

Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice

Knockout of microRNA-21 reduces biliary hyperplasia and liver fibrosis in cholestatic bile duct ligated mice

Dehydroepiandrosterone Activation of G-protein-coupled Estrogen Receptor Rapidly Stimulates MicroRNA-21 Transcription in Human Hepatocellular Carcinoma Cells

Noncoding RNAs in development and teratology, with focus on effects of cannabis, cocaine, nicotine, and ethanol

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