miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell: An essential role for apoptosis

Guo, Can-Jie; Pan, Qin; Li, Ding-Guo; Sun, Hua; Liu, Bowei

doi:10.1016/j.jhep.2008.11.025

Cited by 253 publications

(232 citation statements)

References 26 publications

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“…We have noted that the inhibition of miR-15a or 16 indeed caused a certain degree of apoptosis in both RA and hyperoxic conditions. However, as shown in Figure C, when using the miR-15a/16 dual-knockout cells, a synergistic effect, with previous reports using immunomodulatory cells or tumor cells (32,33) …”

Section: Mir-15a/16 Inhibitors Promote Hyperoxia-induced Apoptosis Insupporting

confidence: 87%

MicroRNA-15a/16 Regulates Apoptosis of Lung Epithelial Cells After Oxidative Stress

Cao

Zhang

Moon

et al. 2016

Mol Med

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Lung epithelial cell apoptosis is an important feature of hyperoxia-induced lung injury. The death receptor-associated extrinsic pathway and mitochondria-associated intrinsic pathway both mediate the development of lung epithelial cell apoptosis. Despite decades of research, molecular mechanisms of hyperoxia-induced epithelial cell apoptosis remain incompletely understood. Here, we report a novel regulatory paradigm in response to hyperoxia-associated oxidative stress. Hyperoxia markedly upregulated microRNA (miR)-15a/16 levels in lung epithelial cells, bronchoalveolar lavage fluid (BALF) and lung tissue. This effect was mediated by hyperoxia-induced reactive oxygen species. Functionally, miR-15a/16 inhibitors induced caspase-3-mediated lung epithelial cell apoptosis, in the presence of hyperoxia. MiR-15a/16 inhibitors robustly enhanced FADD level and downregulated Bcl-2 expression. Consistently, cleaved caspase-8 and -9 were highly induced in the miR-15a/16-deficient cells, after hyperoxia. Using airway epithelial cell-specific, miR-15a/16 -/-mice, we found that Bcl-2 was significantly reduced in lung epithelial cells in vivo after hyperoxia. In contrast, caspase-3, caspase-8 and Bcl-2-associated death promoter (BAD) were highly elevated in the miR-15a/16 -/-epithelial cells in vivo. Interestingly, in lung epithelial malignant cells, rather than benign cells, deletion of miR-15a/16 prevented apoptosis. Furthermore, deletion of miR-15a/16 in macrophages also prohibited apoptosis, which is the opposite of what we have found in normal lung epithelial cells. Taken together, our data suggested that miR-15a/16 may exert differential roles in different cell types. MiR-15a/16 deficiency results in lung epithelial cell apoptosis in response to hyperoxia, via modulating both intrinsic and extrinsic apoptosis pathways.

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Section: Mir-15a/16 Inhibitors Promote Hyperoxia-induced Apoptosis Insupporting

confidence: 87%

MicroRNA-15a/16 Regulates Apoptosis of Lung Epithelial Cells After Oxidative Stress

Cao

Zhang

Moon

et al. 2016

Mol Med

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“…Studies on microRNAs revealed that miR-15b and miR-16 may be essential for apoptosis in activation of rat HSC by targeting Bcl-2 and the caspase signaling pathway (Guo et al, 2009). Over-expression of miRNA-150 and miRNA-194 inhibits HSC activation and ECM production via inhibition of c-myb and rac 1 expression (Venugopal et al, 2009).…”

Section: Inhibition Of Hcc Development By Repression Of Hsc Activationmentioning

confidence: 99%

Hepatic Stellate Cells in Inflammation‐Fibrosis‐Carcinoma Axis

Wang

Cheng

Gao

et al. 2010

The Anatomical Record

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Almost 80% of hepatocellular carcinoma (HCC) cases are associated with chronic hepatitis and cirrhosis resulting from inflammation and fibrosis. A three-step process of ''inflammation-fibrosis-carcinoma'' is believed to be involved in hepatocarcinogenesis. The activation of hepatic stellate cells (HSCs) may serve as an important mediator in the process of inflammation-fibrosis-carcinoma axis, even in tumor metastasis. A remarkable knowledge of activated HSCs in the pathology of HCC development is mostly focused on the liver fibrosis. The molecular links that connects inflammation and cancer in the activation of HSC are not completely known. This highlights urgent need to increase our understanding of the cellular and molecular mechanisms, by which activation of HSCs is involved in the hepatic inflammation, carcinogenesis, and metastasis.

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“…Their regulatory potential is vast: as many as 60% of all mRNAs are predicted to be regulated by miRNAs to some extent (13). The role of miRNAs has been widely studied in the regulation of a broad spectrum of cellular processes, including proliferation and differentiation, cancer, apoptosis, and viral infections (14)(15)(16)(17). Recently, these small RNAs also were found to be involved in the TLR and RIG-I signaling pathways of the innate immune system (18).…”

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confidence: 99%

MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

Zhu

Nie

et al. 2015

The Journal of Immunology

100

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Japanese encephalitis virus (JEV) can target CNS and cause neuroinflammation that is characterized by profound neuronal damage and concomitant microgliosis/astrogliosis. Although microRNAs (miRNAs) have emerged as a major regulatory network with profound effects on inflammatory response, it is less clear how they regulate JEV-induced inflammation. In this study, we found that miR-15b is involved in modulating the JEV-induced inflammatory response. The data demonstrate that miR-15b is upregulated during JEV infection of glial cells and mouse brains. In vitro overexpression of miR-15b enhances the JEV-induced inflammatory response, whereas inhibition of miR-15b decreases it. Mechanistically, ring finger protein 125 (RNF125), a negative regulator of RIG-I signaling, is identified as a direct target of miR-15b in the context of JEV infection. Furthermore, inhibition of RNF125 by miR-15b results in an elevation in RIG-I levels, which, in turn, leads to a higher production of proinflammatory cytokines and type I IFN. In vivo knockdown of virus-induced miR-15b by antagomir-15b restores the expression of RNF125, reduces the production of inflammatory cytokines, attenuates glial activation and neuronal damage, decreases viral burden in the brain, and improves survival in the mouse model. Taken together, our results indicate that miR-15b modulates the inflammatory response during JEV infection by negative regulation of RNF125 expression. Therefore, miR-15b targeting may constitute an interesting and promising approach to control viral-induced neuroinflammation.

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miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell: An essential role for apoptosis

Cited by 253 publications

References 26 publications

MicroRNA-15a/16 Regulates Apoptosis of Lung Epithelial Cells After Oxidative Stress

MicroRNA-15a/16 Regulates Apoptosis of Lung Epithelial Cells After Oxidative Stress

Hepatic Stellate Cells in Inflammation‐Fibrosis‐Carcinoma Axis

MicroRNA-15b Modulates Japanese Encephalitis Virus–Mediated Inflammation via Targeting RNF125

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